Publications by authors named "Frederick Koster"

29 Publications

  • Page 1 of 1

A spatial model of the efficiency of T cell search in the influenza-infected lung.

J Theor Biol 2016 06 23;398:52-63. Epub 2016 Feb 23.

Department of Computer Science, University of New Mexico, Albuquerque, NM, USA; Lovelace Respiratory Research Institute, Albuquerque, NM, USA.

Emerging strains of influenza, such as avian H5N1 and 2009 pandemic H1N1, are more virulent than seasonal H1N1 influenza, yet the underlying mechanisms for these differences are not well understood. Subtle differences in how a given strain interacts with the immune system are likely a key factor in determining virulence. One aspect of the interaction is the ability of T cells to locate the foci of the infection in time to prevent uncontrolled expansion. Here, we develop an agent based spatial model to focus on T cell migration from lymph nodes through the vascular system to sites of infection. We use our model to investigate whether different strains of influenza modulate this process. We calibrate the model using viral and chemokine secretion rates we measure in vitro together with values taken from literature. The spatial nature of the model reveals unique challenges for T cell recruitment that are not apparent in standard differential equation models. In this model comparing three influenza viruses, plaque expansion is governed primarily by the replication rate of the virus strain, and the efficiency of the T cell search-and-kill is limited by the density of infected epithelial cells in each plaque. Thus for each virus there is a different threshold of T cell search time above which recruited T cells are unable to control further expansion. Future models could use this relationship to more accurately predict control of the infection.
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http://dx.doi.org/10.1016/j.jtbi.2016.02.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4862360PMC
June 2016

Spatial-Temporal Distribution of Hantavirus Rodent-Borne Infection by Oligoryzomys fulvescens in the Agua Buena Region--Panama.

PLoS Negl Trop Dis 2016 Feb 19;10(2):e0004460. Epub 2016 Feb 19.

The Emerging Pathogens Institute and Department of Geography, University of Florida, Gainesville, Florida, United States of America.

Background: Hotspot detection and characterization has played an increasing role in understanding the maintenance and transmission of zoonotic pathogens. Identifying the specific environmental factors (or their correlates) that influence reservoir host abundance help increase understanding of how pathogens are maintained in natural systems and are crucial to identifying disease risk. However, most recent studies are performed at macro-scale and describe broad temporal patterns of population abundances. Few have been conducted at a microscale over short time periods that better capture the dynamical patterns of key populations. These finer resolution studies may better define the likelihood of local pathogen persistence. This study characterizes the landscape distribution and spatio-temporal dynamics of Oligoryzomys fulvescens (O. fulvescens), an important mammalian reservoir in Central America.

Methods: Information collected in a longitudinal study of rodent populations in the community of Agua Buena in Tonosí, Panama, between April 2006 and December 2009 was analyzed using non-spatial analyses (box plots) and explicit spatial statistical tests (correlograms, SADIE and LISA). A 90 node grid was built (raster format) to design a base map. The area between the nodes was 0.09 km(2) and the total study area was 6.43 km(2) (2.39 x 2.69 km). The temporal assessment dataset was divided into four periods for each year studied: the dry season, rainy season, and two months-long transitions between seasons (the months of April and December).

Results: There were heterogeneous patterns in the population densities and degrees of dispersion of O. fulvescens that varied across seasons and among years. The species typically was locally absent during the late transitional months of the season, and re-established locally in subsequent years. These populations re-occurred in the same area during the first three years but subsequently re-established further south in the final year of the study. Spatial autocorrelation analyses indicated local populations encompassed approximately 300-600 m. The borders between suitable and unsuitable habitats were sharply demarcated over short distances.

Conclusion: Oligoryzomys fulvescens showed a well-defined spatial pattern that evolved over time, and led to a pattern of changing aggregation. Thus, hot spots of abundance showed a general shifting pattern that helps explain the intermittent risk from pathogens transmitted by this species. This variation was associated with seasonality, as well as anthropogenic pressures that occurred with agricultural activities. These factors help define the characteristics of the occurrence, timing, intensity and duration of synanthropic populations affected by human populations and, consequently, possible exposure that local human populations experience.
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http://dx.doi.org/10.1371/journal.pntd.0004460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760766PMC
February 2016

The rapid and sustained responses of dendritic cells to influenza virus infection in a non-human primate model.

Braz J Infect Dis 2014 Jul-Aug;18(4):406-13. Epub 2014 Apr 26.

Infectious Disease Program, Lovelace Respiratory Research Institute, Albuquerque, NM, USA. Electronic address:

Dendritic cells (DCs) are readily infected by influenza viruses and play a crucial role in regulating host innate and adaptive immune responses to viral infection. The aims of this study are to characterize the dynamic changes in the numbers and maturation status of dendritic cells present in the lung and lung-associated lymph nodes (LALNs) in the model of a non-human primate (NHP) infected by influenza A virus (IAV). Cynomolgus macaques were infected with influenza A virus (H3N2) via bronchoscopy. Flow cytometry was used to analyze the DC numbers, maturation status and subsets during the time of acute infection (days 1, 2, 3, 4, 7) and the resolution phase (day 30). A dramatic increase in the numbers of influenza A virus-infected CD11c+CD14- myeloid dendritic cells (mDCs) and CD11c-CD123+ plasmacytoid dendritic cells (pDCs) were observed from day 1 to day 4 and peak up from day 7 post-infection. In lung and lung-associated lymph nodes, the numbers and maturation status of myeloid dendritic cells and plasmacytoid dendritic cells increased more slowly than those in the lung tissues. On day 30 post-infection, influenza A virus challenge increased the number of myeloid dendritic cells, but not plasmacytoid dendritic cells, compared with baseline. These findings indicate that dendritic cells are susceptible to influenza A virus infection, with the likely purpose of increasing mature myeloid dendritic cells numbers in the lung and lung and lung-associated lymph nodes, which provides important new insights into the regulation of dendritic cells in a non-human primate model.
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http://dx.doi.org/10.1016/j.bjid.2013.12.008DOI Listing
October 2014

Hantavirus fever without pulmonary syndrome in Panama.

Am J Trop Med Hyg 2013 Sep 8;89(3):489-94. Epub 2013 Jul 8.

Epidemiology and Microbiology, Gorgas Memorial Institute for Health Research, Panama City, Panama.

In Panama, hantavirus pulmonary syndrome (HPS) is caused by Choclo virus, a species phylogenetically related to Andes and Maporal viruses. Up to 60% of the population has been positive for specific serum antibody in community-based surveys, but mortality is very uncommon. In four western Panama clinics, we tested individuals presenting with a severe febrile prodrome for acute hantavirus (HV) infection by immunoglobulin M enzyme-linked immunosorbent assay and reverse transcription polymerase chain reaction as well as clinically similar infections, such as dengue and leptospirosis. From 2006 to 2009, at least 21% of 117 patients diagnosed with HV infection had HV Fever (HF) with no evidence of pulmonary edema (no respiratory distress or radiographic lung infiltrates), and 44% of patients had very mild HPS (radiographic pulmonary edema but no respiratory insufficiency). HV infection caused by Choclo virus in Panama presents often as HF, which contrasts with HV in the Americas but is consistent with the high seroprevalence in endemic regions.
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http://dx.doi.org/10.4269/ajtmh.12-0334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3771286PMC
September 2013

Elevated VEGF Levels in Pulmonary Edema Fluid and PBMCs from Patients with Acute Hantavirus Pulmonary Syndrome.

Adv Virol 2012 22;2012:674360. Epub 2012 Aug 22.

Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794-5222, USA.

Hantavirus pulmonary syndrome is characterized by vascular permeability, hypoxia, and acute pulmonary edema. Vascular endothelial growth factor (VEGF) is induced by hypoxia, potently induces vascular permeability, and is associated with high-altitude-induced pulmonary edema. Hantaviruses alter the normal regulation of β3 integrins that restrict VEGF-directed permeability and hantavirus infected endothelial cells are hyperresponsive to the permeabilizing effects of VEGF. However, the role of VEGF in acute pulmonary edema observed in HPS patients remains unclear. Here we retrospectively evaluate VEGF levels in pulmonary edema fluid (PEF), plasma, sera, and PBMCs from 31 HPS patients. VEGF was elevated in HPS patients PEF compared to controls with the highest levels observed in PEF samples from a fatal HPS case. VEGF levels were highest in PBMC samples during the first five days of hospitalization and diminished during recovery. Significantly increased PEF and PBMC VEGF levels are consistent with acute pulmonary edema observed in HPS patients and HPS disease severity. We observed substantially lower VEGF levels in a severe HPS disease survivor after extracorporeal membrane oxygenation. These findings suggest the importance of patients' VEGF levels during HPS, support the involvement of VEGF responses in HPS pathogenesis, and suggest targeting VEGF responses as a potential therapeutic approach.
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http://dx.doi.org/10.1155/2012/674360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3432326PMC
September 2012

Exhaled aerosol transmission of pandemic and seasonal H1N1 influenza viruses in the ferret.

PLoS One 2012 3;7(4):e33118. Epub 2012 Apr 3.

Program in Applied Science, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, United States of America.

Person-to-person transmission of influenza viruses occurs by contact (direct and fomites) and non-contact (droplet and small particle aerosol) routes, but the quantitative dynamics and relative contributions of these routes are incompletely understood. The transmissibility of influenza strains estimated from secondary attack rates in closed human populations is confounded by large variations in population susceptibilities. An experimental method to phenotype strains for transmissibility in an animal model could provide relative efficiencies of transmission. We developed an experimental method to detect exhaled viral aerosol transmission between unanesthetized infected and susceptible ferrets, measured aerosol particle size and number, and quantified the viral genomic RNA in the exhaled aerosol. During brief 3-hour exposures to exhaled viral aerosols in airflow-controlled chambers, three strains of pandemic 2009 H1N1 strains were frequently transmitted to susceptible ferrets. In contrast one seasonal H1N1 strain was not transmitted in spite of higher levels of viral RNA in the exhaled aerosol. Among three pandemic strains, the two strains causing weight loss and illness in the intranasally infected 'donor' ferrets were transmitted less efficiently from the donor than the strain causing no detectable illness, suggesting that the mucosal inflammatory response may attenuate viable exhaled virus. Although exhaled viral RNA remained constant, transmission efficiency diminished from day 1 to day 5 after donor infection. Thus, aerosol transmission between ferrets may be dependent on at least four characteristics of virus-host relationships including the level of exhaled virus, infectious particle size, mucosal inflammation, and viral replication efficiency in susceptible mucosa.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0033118PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3317934PMC
August 2012

Incidence rate for hantavirus infections without pulmonary syndrome, Panama.

Emerg Infect Dis 2011 Oct;17(10):1936-9

Gorgas Memorial Institute for Health Research, Panama City, Panama.

During 2001-2007, to determine incidence of all hantavirus infections, including those without pulmonary syndrome, in western Panama, we conducted 11 communitywide surveys. Among 1,129 persons, antibody prevalence was 16.5%-60.4%. Repeat surveys of 476 found that patients who seroconverted outnumbered patients with hantavirus pulmonary syndrome by 14 to 1.
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http://dx.doi.org/10.3201/eid1710.101717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3310655PMC
October 2011

Transmission of aerosolized seasonal H1N1 influenza A to ferrets.

PLoS One 2011 19;6(9):e24448. Epub 2011 Sep 19.

Program in Infectious Disease, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, United States of America.

Influenza virus is a major cause of morbidity and mortality worldwide, yet little quantitative understanding of transmission is available to guide evidence-based public health practice. Recent studies of influenza non-contact transmission between ferrets and guinea pigs have provided insights into the relative transmission efficiencies of pandemic and seasonal strains, but the infecting dose and subsequent contagion has not been quantified for most strains. In order to measure the aerosol infectious dose for 50% (aID(50)) of seronegative ferrets, seasonal influenza virus was nebulized into an exposure chamber with controlled airflow limiting inhalation to airborne particles less than 5 µm diameter. Airborne virus was collected by liquid impinger and Teflon filters during nebulization of varying doses of aerosolized virus. Since culturable virus was accurately captured on filters only up to 20 minutes, airborne viral RNA collected during 1-hour exposures was quantified by two assays, a high-throughput RT-PCR/mass spectrometry assay detecting 6 genome segments (Ibis T5000™ Biosensor system) and a standard real time RT-qPCR assay. Using the more sensitive T5000 assay, the aID(50) for A/New Caledonia/20/99 (H1N1) was approximately 4 infectious virus particles under the exposure conditions used. Although seroconversion and sustained levels of viral RNA in upper airway secretions suggested established mucosal infection, viral cultures were almost always negative. Thus after inhalation, this seasonal H1N1 virus may replicate less efficiently than H3N2 virus after mucosal deposition and exhibit less contagion after aerosol exposure.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0024448PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3176225PMC
February 2012

Delta inulin polysaccharide adjuvant enhances the ability of split-virion H5N1 vaccine to protect against lethal challenge in ferrets.

Vaccine 2011 Aug 6;29(37):6242-51. Epub 2011 Jul 6.

Infectious Diseases, Lovelace Respiratory Research Institute, Albuquerque, NM 87108, USA.

Background: The reduced immunogenicity of the H5 hemagglutinin (HA), compared to seasonal HA serotypes, has stimulated searches for effective adjuvants to improve H5 vaccine efficacy. This study examined the immunogenicity and protective efficacy in ferrets immunized with a split-virion H5N1 vaccine combined with Advax™, a novel delta inulin-based polysaccharide adjuvant technology that has previously demonstrated ability to augment humoral and cellular immunity to co-administered antigens.

Methods: Ferrets were vaccinated twice 21 days apart with 7.5 μg or 22.5 μg of a split-virion preparation of A/Vietnam/1203/2004 with or without adjuvant. An additional group received just one immunization with 22.5 μg HA plus adjuvant. Serum antibodies were measured by hemagglutination inhibition and microneutralization assays. Vaccinated animals were challenged intranasally 21 days after the last immunization with 10(6) EID(50) of the homologous strain. Morbidity was assessed by observed behavior, weight loss, temperature, cytopenias, histopathology, and viral load.

Results: No serum neutralization antibody was detected after two immunizations with unadjuvanted vaccine. Two immunizations with high or low dose adjuvanted vaccine stimulated high neutralizing antibody titers. Survival was 100% in all groups receiving adjuvanted-vaccine including the single dose group, compared to 67% survival with unadjuvanted vaccine, and 0% survival in saline or adjuvant-alone controls. Minimal morbidity was seen in all animals receiving adjuvanted vaccine, and was limited to rhinorrhea and mild thrombocytopenia, without fever, weight loss, or reduced activity. H5N1 virus was cleared from the nasal wash by day 4 post-challenge only in animals receiving adjuvanted vaccine which also prevented viral invasion of the brain in most animals.

Conclusions: In this initial study, Advax™ adjuvant formulations improved the protective efficacy of a split-virion H5N1 vaccine as measured by significantly enhanced immunogenicity, survival, and reduced morbidity.
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http://dx.doi.org/10.1016/j.vaccine.2011.06.078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3156374PMC
August 2011

Enhanced immunogenicity, mortality protection, and reduced viral brain invasion by alum adjuvant with an H5N1 split-virion vaccine in the ferret.

PLoS One 2011 7;6(6):e20641. Epub 2011 Jun 7.

Infectious Diseases Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, United States of America.

Background: Pre-pandemic development of an inactivated, split-virion avian influenza vaccine is challenged by the lack of pre-existing immunity and the reduced immunogenicity of some H5 hemagglutinins compared to that of seasonal influenza vaccines. Identification of an acceptable effective adjuvant is needed to improve immunogenicity of a split-virion avian influenza vaccine.

Methods And Findings: Ferrets (N = 118) were vaccinated twice with a split-virion vaccine preparation of A/Vietnam/1203/2004 or saline either 21 days apart (unadjuvanted: 1.9 µg, 7.5 µg, 30 µg, or saline), or 28 days apart (unadjuvanted: 22.5 µg, or alum-adjuvanted: 22.5 or 7.5 µg). Vaccinated animals were challenged intranasally 21 or 28 days later with 10(6) EID(50) of the homologous strain. Immunogenicity was measured by hemagglutination inhibition and neutralization assays. Morbidity was assessed by observed behavior, weight loss, temperature, cytopenias, histopathology, and viral load. No serum antibodies were detected after vaccination with unadjuvanted vaccine, whereas alum-adjuvanted vaccination induced a robust antibody response. Survival after unadjuvanted dose regimens of 30 µg, 7.5 µg and 1.9 µg (21-day intervals) was 64%, 43%, and 43%, respectively, yet survivors experienced weight loss, fever and thrombocytopenia. Survival after unadjuvanted dose regimen of 22.5 µg (28-day intervals) was 0%, suggesting important differences in intervals in this model. In contrast to unadjuvanted survivors, either dose of alum-adjuvanted vaccine resulted in 93% survival with minimal morbidity and without fever or weight loss. The rarity of brain inflammation in alum-adjuvanted survivors, compared to high levels in unadjuvanted vaccine survivors, suggested that improved protection associated with the alum adjuvant was due to markedly reduced early viral invasion of the ferret brain.

Conclusion: Alum adjuvant significantly improves efficacy of an H5N1 split-virion vaccine in the ferret model as measured by immunogenicity, mortality, morbidity, and brain invasion.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0020641PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3110201PMC
October 2011

Levofloxacin cures experimental pneumonic plague in African green monkeys.

PLoS Negl Trop Dis 2011 Feb 8;5(2):e959. Epub 2011 Feb 8.

Lovelace Respiratory Research Institute, Albuquerque, New Mexico, United States of America.

Background: Yersinia pestis, the agent of plague, is considered a potential bioweapon due to rapid lethality when delivered as an aerosol. Levofloxacin was tested for primary pneumonic plague treatment in a nonhuman primate model mimicking human disease.

Methods And Results: Twenty-four African Green monkeys (AGMs, Chlorocebus aethiops) were challenged via head-only aerosol inhalation with 3-145 (mean = 65) 50% lethal (LD(50)) doses of Y. pestis strain CO92. Telemetered body temperature >39 °C initiated intravenous infusions to seven 5% dextrose controls or 17 levofloxacin treated animals. Levofloxacin was administered as a "humanized" dose regimen of alternating 8 mg/kg and 2 mg/kg 30-min infusions every 24-h, continuing until animal death or 20 total infusions, followed by 14 days of observation. Fever appeared at 53-165 h and radiographs found multilobar pneumonia in all exposed animals. All control animals died of severe pneumonic plague within five days of aerosol exposure. All 16 animals infused with levofloxacin for 10 days survived. Levofloxacin treatment abolished bacteremia within 24 h in animals with confirmed pre-infusion bacteremia, and reduced tachypnea and leukocytosis but not fever during the first 2 days of infusions.

Conclusion: Levofloxacin cures established pneumonic plague when treatment is initiated after the onset of fever in the lethal aerosol-challenged AGM nonhuman primate model, and can be considered for treatment of other forms of plague. Levofloxacin may also be considered for primary presumptive-use, multi-agent antibiotic in bioterrorism events prior to identification of the pathogen.
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http://dx.doi.org/10.1371/journal.pntd.0000959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3035670PMC
February 2011

Higher level of replication efficiency of 2009 (H1N1) pandemic influenza virus than those of seasonal and avian strains: kinetics from epithelial cell culture and computational modeling.

J Virol 2011 Jan 10;85(2):1125-35. Epub 2010 Nov 10.

Infectious Disease Program, Lovelace Respiratory Research Institute, 2425 Ridgecrest Dr. SE, Albuquerque, NM 87108, USA.

The pathogenicity and transmission of influenza A viruses are likely determined in part by replication efficiency in human cells, which is the net effect of complex virus-host interactions. H5N1 avian, H1N1 seasonal, and H1N1 2009 pandemic influenza virus strains were compared by infecting human differentiated bronchial epithelial cells in air-liquid interface cultures at relatively low virus particle/cell ratios. Differential equation and computational models were used to characterize the in vitro kinetic behaviors of the three strains. The models were calibrated by fitting experimental data in order to estimate difficult-to-measure parameters. Both models found marked differences in the relative values of p, the virion production rate per cell, and R(0), an index of the spread of infection through the monolayer, with the values for the strains in the following rank order (from greatest to least): pandemic strain, followed by seasonal strain, followed by avian strain, as expected. In the differential equation model, which treats virus and cell populations as well mixed, R(0) and p varied proportionately for all 3 strains, consistent with a primary role for productivity. In the spatially explicit computational model, R(0) and p also varied proportionately except that R(0) derived for the pandemic strain was reduced, consistent with constrained viral spread imposed by multiple host defenses, including mucus and paracrine antiviral effects. This synergistic experimental-computational strategy provides relevant parameters for identifying and phenotyping potential pandemic strains.
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http://dx.doi.org/10.1128/JVI.01722-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3019989PMC
January 2011

Primary pneumonic plague in the African Green monkey as a model for treatment efficacy evaluation.

J Med Primatol 2011 Feb 16;40(1):6-17. Epub 2010 Aug 16.

Lovelace Respiratory Research Institute, Albuquerque, NM, USA.

Background: Primary pneumonic plague is rare among humans, but treatment efficacy may be tested in appropriate animal models under the FDA 'Animal Rule'.

Methods: Ten African Green monkeys (AGMs) inhaled 44-255 LD(50) doses of aerosolized Yersinia pestis strain CO92. Continuous telemetry, arterial blood gases, chest radiography, blood culture, and clinical pathology monitored disease progression.

Results: Onset of fever, >39°C detected by continuous telemetry, 52-80 hours post-exposure was the first sign of systemic disease and provides a distinct signal for treatment initiation. Secondary endpoints of disease severity include tachypnea measured by telemetry, bacteremia, extent of pneumonia imaged by chest x-ray, and serum lactate dehydrogenase enzyme levels.

Conclusions: Inhaled Y. pestis in the AGM results in a rapidly progressive and uniformly fatal disease with fever and multifocal pneumonia, serving as a rigorous test model for antibiotic efficacy studies.
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http://dx.doi.org/10.1111/j.1600-0684.2010.00443.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2991483PMC
February 2011

Confirmation of Choclo virus as the cause of hantavirus cardiopulmonary syndrome and high serum antibody prevalence in Panama.

J Med Virol 2010 Sep;82(9):1586-93

Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico.

Choclo virus (CHOV) was described in sigmodontine rodents, Oligoryzomys fulvescens, and humans during an outbreak of hantavirus cardiopulmonary syndrome (HCPS) in 1999-2000 in western Panama. Although HCPS is rare, hantavirus-specific serum antibody prevalence among the general population is high suggesting that CHOV may cause many mild or asymptomatic infections. The goals of this study were to confirm the role of CHOV in HCPS and in the frequently detected serum antibody and to establish the phylogenetic relationship with other New World hantaviruses. CHOV was cultured to facilitate the sequencing of the small (S) and medium (M) segments and to perform CHOV-specific serum neutralization antibody assays. Sequences of the S and M segments found a close relationship to other Oligoryzomys-borne hantaviruses in the Americas, highly conserved terminal nucleotides, and no evidence for recombination events. The maximum likelihood and maximum parsimony analyses of complete M segment nucleotide sequences indicate a close relationship to Maporal and Laguna Negra viruses, found at the base of the South American clade. In a focus neutralization assay acute and convalescent sera from six Panamanian HCPS patients neutralized CHOV in dilutions from 1:200 to 1:6,400. In a sample of antibody-positive adults without a history of HCPS, 9 of 10 sera neutralized CHOV in dilutions ranging from 1:100 to 1:6,400. Although cross-neutralization with other sympatric hantaviruses not yet associated with human disease is possible, CHOV appears to be the causal agent for most of the mild or asymptomatic hantavirus infections, as well as HCPS, in Panama.
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http://dx.doi.org/10.1002/jmv.21864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2927102PMC
September 2010

Convalescent pulmonary dysfunction following hantavirus pulmonary syndrome in Panama and the United States.

Lung 2010 Oct 4;188(5):387-91. Epub 2010 Jun 4.

Ministry of Health, Panama City, Republic of Panama.

The objective of this study was to document persistent pulmonary symptoms and pulmonary function abnormalities in adults surviving hantavirus pulmonary syndrome (HPS). Acute infection by most hantaviruses result in mortality rates of 25-35%, while in Panama the mortality rate of 10% is contrasted by an unusually high incidence. In all types of HPS, the viral prodrome, cardiopulmonary phase due to massive pulmonary capillary leak syndrome, and spontaneous diuresis are followed by a convalescent phase with exertional dyspnea for 3-4 weeks, but the frequency of persistent symptoms is not known. In this observational study of a convenience sample, 14 survivors of HPS caused by Choclo virus infection in Panama and 9 survivors of HPS caused by Sin Nombre virus infection in New Mexico completed a questionnaire and pulmonary function tests up to 8 years after infection. In both groups, exertional dyspnea persisted for 1-2 years after acute infection in 43% (Panama) and 77% (New Mexico) of survivors surveyed. Reduction in midexpiratory flows (FEF(25-75%)), increased residual volume (RV), and reduced diffusion capacity (D(L)CO/VA) also were common in both populations; but the severity of reduced expiratory flow did not correlate with exertional dyspnea. Symptoms referable to previous hantavirus infection had resolved within 3 years of acute infection in most but not all patients in the Panama group. Temporary exertional dyspnea and reduced expiratory flow are common in early convalescence after HPS but resolves in almost all patients.
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http://dx.doi.org/10.1007/s00408-010-9245-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2939327PMC
October 2010

Milestones in progression of primary pneumonic plague in cynomolgus macaques.

Infect Immun 2010 Jul 12;78(7):2946-55. Epub 2010 Apr 12.

Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108, USA.

Vaccines against primary pneumonic plague, a potential bioweapon, must be tested for efficacy in well-characterized nonhuman primate models. Telemetered cynomolgus macaques (Macaca fascicularis) were challenged by the aerosol route with doses equivalent to approximately 100 50% effective doses of Yersinia pestis strain CO92 and necropsied at 24-h intervals postexposure (p.e.). Data for telemetered heart rates, respiratory rates, and increases in the temperature greater than the diurnal baseline values identified the onset of the systemic response at 55 to 60 h p.e. in all animals observed for at least 70 h p.e. Bacteremia was detected at 72 h p.e. by a Yersinia 16S rRNA-specific quantitative reverse transcription-PCR and was detected later by the culture method at the time of moribund necropsy. By 72 h p.e. multilobar pneumonia with diffuse septal inflammation consistent with early bacteremia was established, and all lung tissues had a high bacterial burden. The levels of cytokines or chemokines in serum were not significantly elevated at any time, and only the interleukin-1beta, CCL2, and CCL3 levels were elevated in lung tissue. Inhalational plague in the cynomolgus macaque inoculated by the aerosol route produces most clinical features of the human disease, and in addition the disease progression mimics the disease progression from the anti-inflammatory phase to the proinflammatory phase described for the murine model. Defined milestones of disease progression, particularly the onset of fever, tachypnea, and bacteremia, should be useful for evaluating the efficacy of candidate vaccines.
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http://dx.doi.org/10.1128/IAI.01296-09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2897392PMC
July 2010

Hantavirus infection and habitat associations among rodent populations in agroecosystems of Panama: implications for human disease risk.

Am J Trop Med Hyg 2009 Jul;81(1):59-66

Department of Population Medicine, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota 55108, USA.

Hantavirus cardiopulmonary syndrome (HCPS), which is caused by infection with Choclo virus, is uncommon in Panama, yet seropositivity among rural residents is as high as 60%. To clarify the environmental risk factors favoring rodent-to-human transmission, we tested serum from 3,067 rodents captured over a five-year period for antibodies against recombinant N protein of hantavirus by enzyme immunoassay and strip immunoblot. Among 220 seropositive rodents, Oligoryzomys fulvescens, the reservoir of Choclo virus, had the highest overall seroprevalence (23.5%); more abundant rodents (Zygodontomys brevicauda and Sigmodon hirsutus) had lower seroprevalences. In the mixed (combined modern and traditional) productive agroecosystem, the highest seroprevalence was among O. fulvescens captured in residences and in crops grown within 40 meters of a residence, with significantly lower seroprevalence in adjacent pasture and non-productive vegetation. Thus, crop habitats may serve as refugia for invasion into adjacent human residences and suggests several interventions to reduce human infection.
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July 2009

Immunization with recombinant V10 protects cynomolgus macaques from lethal pneumonic plague.

Infect Immun 2008 Dec 15;76(12):5588-97. Epub 2008 Sep 15.

Department of Microbiology, University of Chicago, Chicago, Illinois 60637, USA.

Vaccine and therapeutic strategies that prevent infections with Yersinia pestis have been sought for over a century. Immunization with live attenuated (nonpigmented) strains and immunization with subunit vaccines containing recombinant low-calcium-response V antigen (rLcrV) and recombinant F1 (rF1) antigens are considered effective in animal models. Current antiplague subunit vaccines in development for utilization in humans contain both antigens, either as equal concentrations of the two components (rF1 plus rLcrV) or as a fusion protein (rF1-rLcrV). Here, we show that immunization with either purified rLcrV (a protein at the tip of type III needles) or a variant of this protein, recombinant V10 (rV10) (lacking amino acid residues 271 to 300), alone or in combination with rF1, prevented pneumonic lesions and disease pathogenesis. In addition, passive immunization studies showed that specific antibodies of macaques immunized with rLcrV, rV10, or rF1, either alone or in combination, conferred protection against bubonic plague challenge in mice. Finally, we found that when we compared the reactivities of anti-rLcrV and anti-rV10 immune sera from cynomolgus macaques, BALB/c mice, and brown Norway rats with LcrV-derived peptides, rV10, but not rLcrV immune sera, lacked antibodies recognizing linear LcrV oligopeptides.
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http://dx.doi.org/10.1128/IAI.00699-08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2583586PMC
December 2008

Choclo virus infection in the Syrian golden hamster.

Am J Trop Med Hyg 2008 Apr;78(4):669-74

University of Texas Medical Branch, Department of Pathology, Galveston, Texas 77555-0609, USA.

Andes virus and Choclo virus are agents of hantavirus pulmonary syndrome. Andes virus in hamsters almost always causes a disease that is pathologically indistinguishable from fatal hantavirus pulmonary syndrome. The purpose of this study was to assess the pathogenicity of Choclo virus in hamsters. None of 18 hamsters infected with Choclo virus exhibited any symptom of disease. No evidence of inflammation or edema was found in the lungs of the 10 animals killed on days 7, 9, 11, 13, and 16 post-inoculation or in the lungs of the 8 animals killed on day 28 post-inoculation; however, hantavirus antigen was present in large numbers of endothelial cells in the microvasculature of the lungs of the animals killed on days 7, 9, 11, and 13 post-inoculation. These results suggest that infection in the microvasculature of lung tissue alone does not result in the life-threatening pulmonary edema in hamsters infected with Andes virus.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2689364PMC
April 2008

Hantavirus cardiopulmonary syndrome.

Semin Respir Crit Care Med 2007 Apr;28(2):193-200

Department of Internal Medicine, University of New Mexico Health Science Center, Albuquerque, New Mexico, USA.

Hantavirus cardiopulmonary syndrome (HCPS) is caused by infection with multiple types of hantaviruses throughout the Americas. All strains induce a pulmonary capillary leak syndrome with cardiogenic shock in severe cases, and almost all strains have an overall mortality rate of 35%. Some strains in South America are commonly associated with either mild disease without pulmonary edema or severe disease with pulmonary hemorrhage. Early recognition during the thrombocytopenic prodrome phase and transport to intensive care improve survival, due to very rapid progression of respiratory failure and shock in some patients. Limited fluid replacement, early inotropic therapy, and mechanical ventilation also improve survival. Extracorporeal membrane oxygenation (ECMO) has been life saving for patients with refractory shock. Ribavirin does not appear to reduce mortality, but hyperimmune serum offers a promising future therapy because survival is correlated with higher neutralizing antibody titers at admission.
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http://dx.doi.org/10.1055/s-2007-976491DOI Listing
April 2007

Computer-aided diagnosis with potential application to rapid detection of disease outbreaks.

Stat Med 2007 Apr;26(8):1857-74

Los Alamos National Laboratory, Mail Stop F600, Los Alamos, NM 87545, USA.

Our objectives are to quickly interpret symptoms of emergency patients to identify likely syndromes and to improve population-wide disease outbreak detection. We constructed a database of 248 syndromes, each syndrome having an estimated probability of producing any of 85 symptoms, with some two-way, three-way, and five-way probabilities reflecting correlations among symptoms. Using these multi-way probabilities in conjunction with an iterative proportional fitting algorithm allows estimation of full conditional probabilities. Combining these conditional probabilities with misdiagnosis error rates and incidence rates via Bayes theorem, the probability of each syndrome is estimated. We tested a prototype of computer-aided differential diagnosis (CADDY) on simulated data and on more than 100 real cases, including West Nile Virus, Q fever, SARS, anthrax, plague, tularaemia and toxic shock cases. We conclude that: (1) it is important to determine whether the unrecorded positive status of a symptom means that the status is negative or that the status is unknown; (2) inclusion of misdiagnosis error rates produces more realistic results; (3) the naive Bayes classifier, which assumes all symptoms behave independently, is slightly outperformed by CADDY, which includes available multi-symptom information on correlations; as more information regarding symptom correlations becomes available, the advantage of CADDY over the naive Bayes classifier should increase; (4) overlooking low-probability, high-consequence events is less likely if the standard output summary is augmented with a list of rare syndromes that are consistent with observed symptoms, and (5) accumulating patient-level probabilities across a larger population can aid in biosurveillance for disease outbreaks.
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http://dx.doi.org/10.1002/sim.2798DOI Listing
April 2007

Modeling intercellular interactions in early Mycobacterium infection.

Bull Math Biol 2006 Nov 20;68(8):2233-61. Epub 2006 May 20.

Department of Computer Science, University of New Mexico, P.O. Box 5800 MS 1423, Albuquerque, NM 87185-1423, USA.

Infection with Mycobacterium tuberculosis (Mtb) is characterized by localized, roughly spherical lesions within which the pathogen interacts with host cells. Containment of the infection or progression of disease depends on the behavior of individual cells, which, in turn, depends on the local molecular environment and on contact with neighboring cells. Modeling can help us understand the nonlinear interactions that drive the overall dynamics in this system. Early events in infection are particularly important, as are spatial effects and inherently stochastic processes. We describe a model of early Mycobacterium infection using the CyCells simulator, which was designed to capture these effects. We relate CyCells simulations of the model to several experimental observations of individual components of the response to Mtb.
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http://dx.doi.org/10.1007/s11538-006-9103-yDOI Listing
November 2006

Characterization of shock in a hamster model of hantavirus infection.

Virology 2006 Dec 5-20;356(1-2):45-9. Epub 2006 Sep 6.

Pathophysiology Division, Lovelace Respiratory Research Institute, 2425 Ridgecrest Dr. SE, Albuquerque, NM 87108, USA.

Human hantavirus cardiopulmonary syndrome (HCPS) due to Andes, sin nombre and other hantaviruses is characterized by severe pulmonary capillary leak and cardiogenic shock. Hamsters, the only animal manifesting HCPS-like disease, were instrumented with radiotelemeters that enabled ambulatory intracarotid blood pressure recording within an animal biosafety level-4 facility. Following infection with Andes virus, blood pressure and heart rate decreased slowly in a biphasic manner during the first 7 days of infection, followed by a rapid fall in pressure and rapid increase in heart rate during the 10-20 h preceding death on day 9 or 10. The preterminal narrowing of pulse pressure was consistent with a cardiogenic impairment. Heart rate variability analysis implicated increased sympathetic nervous system activity as seen in human HCPS. The hamster model of HCPS mimics not only the pulmonary capillary leak but also the hypotension characteristic of human HCPS.
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http://dx.doi.org/10.1016/j.virol.2006.07.044DOI Listing
January 2007

Rodent-associated Bartonella febrile illness, Southwestern United States.

Emerg Infect Dis 2006 Jul;12(7):1081-6

US Public Health Service, Gallup, New Mexico, USA.

Serum specimens from 114 patients hospitalized with a febrile illness were tested with an indirect immunofluorescence assay (IFA) using Bartonella antigens prepared from 6 species of sigmodontine rodents and 3 known human Bartonella pathogens: B. henselae, B. quintana, and B. elizabethae. Acute- and convalescent-phase serum samples from 5 of these patients showed seroconversion with an IFA titer >512 to rodent-associated Bartonella antigens. The highest titer was against antigen derived from the white-throated woodrat (Neotoma albigula), although this rodent is not necessarily implicated as the source of infection. Three of the 5 who seroconverted showed no cross-reaction to the 3 Bartonella human pathogens. Common clinical characteristics were fever, chills, myalgias, leukopenia, thrombocytopenia, and transaminasemia. Although antibodies to Bartonella are cross-reactive, high-titer seroconversions to rodent-associated Bartonella antigens in adults with common clinical characteristics should stimulate the search for additional Bartonella human pathogens.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291043PMC
http://dx.doi.org/10.3201/eid1207.040397DOI Listing
July 2006

Placebo-controlled, double-blind trial of intravenous ribavirin for the treatment of hantavirus cardiopulmonary syndrome in North America.

Clin Infect Dis 2004 Nov 11;39(9):1307-13. Epub 2004 Oct 11.

Internal Medicine, University of New Mexico, Albuquerque, New Mexico 87131-0001, USA.

Unlabelled: BACKGROUND. Ribavirin is active in vitro against hantaviruses, but the findings of an open trial of the use of intravenous ribavirin for the treatment of hantavirus cardiopulmonary syndrome (HCPS) were inconclusive.

Methods: Subjects with suspected HCPS in the prodrome or cardiopulmonary phase but without shock were eligible for randomization to receive either intravenous ribavirin (33 mg/kg [
Results: Thirty-six subjects were enrolled in the trial from March 1996 through July 2001, at which point the study was terminated prematurely because of both the slow rate of accrual of subjects and the findings of a futility analysis. Of the 36 subjects enrolled, 23 (all of whom were enrolled during the cardiopulmonary stage of HCPS) had HCPS confirmed by serologic testing. The severity of illness at entry into the study was similar among the 10 subjects with HCPS who received ribavirin and the 13 subjects with HCPS who received placebo. The proportion of subjects who survived and who did not require ECMO was similar among ribavirin recipients and placebo recipients (70% vs. 62%, respectively); 2 ribavirin recipients and 2 placebo recipients died, including 3 of 7 subjects treated with ECMO. The frequency of adverse events, including anemia, was similar between treatment groups.

Conclusions: The rate of accrual of subjects in the present study was inadequate to clearly assess the safety or efficacy of ribavirin in the treatment of HCPS. However, ribavirin was well tolerated, and the lack of trends supporting the use of intravenous ribavirin suggests that it is probably ineffective in the treatment of HCPS in the cardiopulmonary stage.
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http://dx.doi.org/10.1086/425007DOI Listing
November 2004

High seroprevalence of hantavirus infection on the Azuero peninsula of Panama.

Am J Trop Med Hyg 2004 Jun;70(6):682-7

Gorgas Memorial Institute of Health Studies, Panama City, Panama.

The first outbreak of hantavirus pulmonary syndrome (HPS) in Central America was documented on the Azuero peninsula of Panama in late 1999 and 2000. Reverse transcriptase-polymerase chain reaction evidence implicated only Choclo virus in symptomatic HPS with a mortality rate of 20%, although two rodent-borne hantaviruses (Choclo virus and Calabazo virus) were identified in the peridomestic habitat. Neighborhood serosurveys around case households found seroprevalence rates as high as 30%, the highest in the Americas except for western Paraguay. We report here population-based serosurveys for 1,346 adults and children in four communities, three on the Azuero peninsula and one in adjacent central Panama. Overall seroprevalence ranged from 33.2% in a population engaged in farming and fishing on Isla de Cañas, to 16.3% and 21.2% in two mainland agricultural communities, to 3.1% in central Panama, with a modest male predominance of 1.2:1. Nine percent of children 4-10 years old were seropositive, and seroprevalence increased with age in all communities, with highest levels of 52% in those 41-50 years old cohort on Isla de Cañas. Univariate analysis identified correlations between seroprevalence and multiple agricultural and animal husbandry activities. However, stepwise logistic regression models identified only raising animals (cows, pigs, goats, poultry) and fishing as significant independent variables. Human infection with hantavirus on the Azuero peninsula, either with Choclo virus or combined with Calabazo virus, is frequent but rarely results in hospitalization due to respiratory illnesses resembling HPS.
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June 2004

Role of specific CD8+ T cells in the severity of a fulminant zoonotic viral hemorrhagic fever, hantavirus pulmonary syndrome.

J Immunol 2004 Mar;172(5):3297-304

Center for Infectious Disease and Vaccine Research, and Department of Pediatrics and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.

We report on the role of specific CD8(+) T cells in the pathogenesis of a highly lethal human viral disease, hantavirus pulmonary syndrome (HPS). HPS is a zoonotic disease caused by transmission of Sin Nombre virus (SNV) from chronically infected deer mice. In humans, this fulminant infection is characterized by lung capillary leakage, respiratory failure, and cardiogenic shock. Individuals with HLA-B*3501 have an increased risk of developing severe HPS, suggesting that CD8(+) T cell responses to SNV contribute to pathogenesis. We identified three CD8(+) T cell epitopes in SNV presented by HLA-B*3501 and quantitated circulating SNV-specific CD8(+) T cells in 11 acute HPS patients using HLA/peptide tetramers. We found significantly higher frequencies of SNV-specific T cells in patients with severe HPS requiring mechanical ventilation (up to 44.2% of CD8(+) T cells) than in moderately ill HPS patients hospitalized but not requiring mechanical ventilation (up to 9.8% of CD8(+) T cells). These results imply that virus-specific CD8(+) T cells contribute to HPS disease outcome. Intense CD8(+) T cell responses to SNV may be induced by the encounter of the unnatural human host to this zoonotic virus without coevolution. This may also be the immunopathologic basis of other life-threatening human virus infections.
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http://dx.doi.org/10.4049/jimmunol.172.5.3297DOI Listing
March 2004

Schistosomiasis in expatriates in the Arusha region of Tanzania.

J Travel Med 2002 Sep-Oct;9(5):233-5

Department of Infectious Diseases, University of New Mexico, Albuquerque, New Mexico 87131, USA.

Background: In 1996 the seroprevalence of schistosomiasis in expatriates and travelers who had contact with Lake Malawi, a fresh water source thought to be schistosomiasis-free, was measured at 32%. Clinicians in Arusha, Tanzania, questioned the prevalence of Schistosoma infection in expatriates living in the Arusha region, and how schistosomiasis might relate to symptoms of chronic fatigue in Arusha expatriates.

Method: We performed a cross-sectional survey of 80 expatriates living in the Arusha region of Tanzania to determine the seroprevalence of schistosome infection. Whole blood was analyzed by the Falcon assay screening test-enzyme-linked immunosorbent assay (FAST-ELISA) for the presence of species-specific Schistosoma mansoni and Schistosoma haematobium antibodies to microsomal antigens of adult Schistosoma worms, followed by confirmatory enzyme-linked immunoelectrotransfer blot (Western blot). Volunteers answered a questionnaire which included length of residence in Arusha, risk factors, symptoms, and previous diagnosis of schistosomiasis.

Results: Of the 80 expatriates sampled, 8 (10%) were positive for schistosomiasis (6 to S. mansoni only, 1 to S. haematobium, 1 to both species). Significant risk factors, elicited by questionnaire, included longer residence in the Arusha region (p =.020), history of fatigue (p =.010) and myalgias (p =.047), and previous diagnosis of schistosomiasis by stool or urine ova (p =.0007).

Conclusion: The lower seroprevalence of schistosomiasis in Arusha expatriates, compared with expatriates and travelers to Lake Malawi, suggests a regional variation of rate of schistosomiasis infection. Although a history of fatigue and myalgias was related to seropositivity, there is no strong evidence that schistosomiasis infection is the cause of chronic fatigue in Arusha expatriates.
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http://dx.doi.org/10.2310/7060.2002.24178DOI Listing
October 2003
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