Publications by authors named "Jaime Inostroza"

16 Publications

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Exploring the Impact of Ketodeoxynonulosonic Acid in Host-Pathogen Interactions Using Uptake and Surface Display by Nontypeable Haemophilus influenzae.

mBio 2021 01 19;12(1). Epub 2021 Jan 19.

Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California, USA

Surface expression of the common vertebrate sialic acid (Sia) -acetylneuraminic acid (Neu5Ac) by commensal and pathogenic microbes appears structurally to represent "molecular mimicry" of host sialoglycans, facilitating multiple mechanisms of host immune evasion. In contrast, ketodeoxynonulosonic acid (Kdn) is a more ancestral Sia also present in prokaryotic glycoconjugates that are structurally quite distinct from vertebrate sialoglycans. We detected human antibodies against Kdn-terminated glycans, and sialoglycan microarray studies found these anti-Kdn antibodies to be directed against Kdn-sialoglycans structurally similar to those on human cell surface Neu5Ac-sialoglycans. Anti-Kdn-glycan antibodies appear during infancy in a pattern similar to those generated following incorporation of the nonhuman Sia -glycolylneuraminic acid (Neu5Gc) onto the surface of nontypeable (NTHi), a human commensal and opportunistic pathogen. NTHi grown in the presence of free Kdn took up and incorporated the Sia into its lipooligosaccharide (LOS). Surface display of the Kdn within NTHi LOS blunted several virulence attributes of the pathogen, including Neu5Ac-mediated resistance to complement and whole blood killing, complement C3 deposition, IgM binding, and engagement of Siglec-9. Upper airway administration of Kdn reduced NTHi infection in human-like null (Neu5Gc-deficient) mice that express a Neu5Ac-rich sialome. We propose a mechanism for the induction of anti-Kdn antibodies in humans, suggesting that Kdn could be a natural and/or therapeutic "Trojan horse" that impairs colonization and virulence phenotypes of free Neu5Ac-assimilating human pathogens. All cells in vertebrates are coated with a dense array of glycans often capped with sugars called sialic acids. Sialic acids have many functions, including serving as a signal for recognition of "self" cells by the immune system, thereby guiding an appropriate immune response against foreign "nonself" and/or damaged cells. Several pathogenic bacteria have evolved mechanisms to cloak themselves with sialic acids and evade immune responses. Here we explore a type of sialic acid called "Kdn" (ketodeoxynonulosonic acid) that has not received much attention in the past and compare and contrast how it interacts with the immune system. Our results show potential for the use of Kdn as a natural intervention against pathogenic bacteria that take up and coat themselves with external sialic acid from the environment.
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http://dx.doi.org/10.1128/mBio.03226-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845648PMC
January 2021

Overnutrition in Infants Is Associated With High Level of Leptin, Viral Coinfection and Increased Severity of Respiratory Infections: A Cross-Sectional Study.

Front Pediatr 2020 18;8:44. Epub 2020 Feb 18.

Facultad de Ciencias de la Salud, Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile.

To investigate the relationship of overnutrition (obese and overweight) with severity of illness in children hospitalized with acute lower respiratory infections (ALRIs), frequency of viral coinfections and leptin levels. We studied 124 children <2 years old that were hospitalized for ALRI. Nutritional status was calculated by z-scores according to weight-for-age z-scores, length or height-for-age z-scores, and weight-for-height z-scores. Nasopharyngeal aspirates (NPAs) were obtained and viral respiratory pathogens were identified using reverse transcription polymerase chain reactions (RT-PCR). Respiratory syncytial virus (RSV) load was assessed using quantitative RT-PCR. NPA and plasma leptin level were measured. Clinical data and nutritional status were recorded, and patients were followed up until hospital discharge. Viral coinfection was defined as the presence of two or more viruses detected in the same respiratory sample. Severity of illness was determined by length of hospitalization and duration of oxygen therapy. Children with overnutrition showed a greater frequency of viral coinfection than those with normal weight (71% obese vs. 37% normal weight = 0.013; 68% overweight vs. 37% normal weight = 0.004). A lower RSV load was found in obese (5.91 log copies/mL) and overweight children (6.49 log copies/mL) compared to normal weight children (8.06 log copies/mL; = 0.021 in both cases). In multivariate analysis, obese, and overweight infants <6 months old were associated with longer hospital stays (RR = 1.68; CI: 1.30-2.15 and obese: RR = 1.68; CI: 1.01-2.71, respectively) as well as a greater duration of oxygen therapy (RR = 1.80; IC: 1.41-2.29 and obese: RR = 1.91; CI: 1.15-3.15, respectively). Obese children <6 months showed higher plasma leptin level than normal weight children (7.58 vs. 5.12 ng/μl; <0.046). In infants younger than 6 months, overnutrition condition was related to increased severity of infections and high plasma leptin level. Also, children with overnutrition showed a greater frequency of viral coinfection and low RSV viral load compared to normal weights children. These findings further contribute to the already existent evidence supporting the importance of overnutrition prevention in pediatric populations.
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http://dx.doi.org/10.3389/fped.2020.00044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041426PMC
February 2020

Chile's National Advisory Committee on Immunization (CAVEI): Evidence-based recommendations for public policy decision-making on vaccines and immunization.

Vaccine 2019 07 29;37(32):4646-4650. Epub 2019 Jun 29.

Departamento de Inmunizaciones, Ministerio de Salud, Monjitas 565, p7, Santiago, Chile. Electronic address:

A National Immunization Technical Advisory Group (NITAG) provides independent, evidence-based recommendations to the Ministry of Health for immunization programmes and policy formulation. In this article, we describe the structure, functioning and work processes of Chile's NITAG (CAVEI) and assess its functionality, quality of work processes and outputs, and integration of the committee into the Ministry of Health policy process using the Assessment tool for National Immunization Technical Advisory Groups. Among its strengths, CAVEI's administrative and work plasticity allows it to respond in a timely manner to the Ministry of Health's requests and proactively raise subjects for review. Representation of multiple areas of expertise within the committee makes CAVEI a robust and balanced entity for the development of evidence-based comprehensive recommendations. High ranking profile of the Secretariat structure furthers CAVEI's competences in policymaking and serves as a bridge between the committee and international initiatives in the field of immunizations.
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http://dx.doi.org/10.1016/j.vaccine.2019.06.069DOI Listing
July 2019

Tuberculosis and impaired IL-23-dependent IFN-γ immunity in humans homozygous for a common missense variant.

Sci Immunol 2018 12;3(30)

St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA.

Inherited IL-12Rβ1 and TYK2 deficiencies impair both IL-12- and IL-23-dependent IFN-γ immunity and are rare monogenic causes of tuberculosis, each found in less than 1/600,000 individuals. We show that homozygosity for the common P1104A allele, which is found in about 1/600 Europeans and between 1/1000 and 1/10,000 individuals in regions other than East Asia, is more frequent in a cohort of patients with tuberculosis from endemic areas than in ethnicity-adjusted controls ( = 8.37 × 10; odds ratio, 89.31; 95% CI, 14.7 to 1725). Moreover, the frequency of P1104A in Europeans has decreased, from about 9% to 4.2%, over the past 4000 years, consistent with purging of this variant by endemic tuberculosis. Surprisingly, we also show that TYK2 P1104A impairs cellular responses to IL-23, but not to IFN-α, IL-10, or even IL-12, which, like IL-23, induces IFN-γ via activation of TYK2 and JAK2. Moreover, TYK2 P1104A is properly docked on cytokine receptors and can be phosphorylated by the proximal JAK, but lacks catalytic activity. Last, we show that the catalytic activity of TYK2 is essential for IL-23, but not IL-12, responses in cells expressing wild-type JAK2. In contrast, the catalytic activity of JAK2 is redundant for both IL-12 and IL-23 responses, because the catalytically inactive P1057A JAK2, which is also docked and phosphorylated, rescues signaling in cells expressing wild-type TYK2. In conclusion, homozygosity for the catalytically inactive P1104A missense variant of selectively disrupts the induction of IFN-γ by IL-23 and is a common monogenic etiology of tuberculosis.
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http://dx.doi.org/10.1126/sciimmunol.aau8714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341984PMC
December 2018

[Recurrent respiratory papillomatosis in a pediatric patient: case report].

Rev Chil Pediatr 2017 Jun;88(3):393-397

Laboratorio de Inmunodeficiencias Primarias, Centro Jeffrey Modell para Diagnóstico de Inmunodeficiencias Primarias, Centro de Excelencia en Medicina Traslacional, Facultad de Medicina, Universidad de La Frontera, Temuco, Chile.

Genetic variability related to the host immune system has been proposed as one of the most influential factors in the development of diseases caused by HPV.

Clinical Case: We report the case of a 5-year-old child in whom chronic laryngeal papillomatosis, probably acquired vertically during labor, was detected. The diagnosis of laryngeal papillomatosis was confirmed with a biopsy after a first surgery to remove the papillomas. The Derkay classification system was used to assess the severity of papillomatosis. Biopsy genotyping was performed by demonstrating HPV-6. Later, HLA-DQA1 * 0505, -DQB1 * 0301, -DRB1 * 1101 alleles were homozygous for HLA allele typing.

Conclusions: Further studies are needed to identify the most prevalent HLA alleles in the Latino population and their potential association with genetic susceptibility in Recurrent Respiratory Papillomatosis.
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http://dx.doi.org/10.4067/S0370-41062017000300013DOI Listing
June 2017

[Specific antibody deficiency: Primary immunodeficiency associated to respiratory allergy].

Rev Chil Pediatr 2017 Apr;88(2):252-257

Centro Jeffrey Modell para Diagnóstico e Investigación en Inmunodeficiencias Primarias, Facultad de Medicina, Universidad de La Frontera, Temuco, Chile.

Specific antibody deficiency (SAD) with normal immunoglobulin and normal B cells is a primary immunodeficiency characterized by reduced ability to produce antibodies to specific antigens especially polysaccharides.

Objective: To describe the characteristics of patients diagnosed with SAD emphasizing the association between primary immunodeficiency and allergic diseases.

Patients And Method: Descriptive study showing patients with SAD treated at a public hospital between August 2007 and July 2015. Other secondary or primary immunodeficiency was discarded. The diagnosis of SAD was based on recurrent infections and abnormal response to pneumococcal polysaccharide vaccine assessed by specific IgG to 10 pneumococcal serotypes.

Results: Twelve patients were included, 4 males, mean age 6 years, recurrent pneumonia predominated (91.7%) as well as other respiratory and invasive infections. All patients with SAD had associated asthma, 11 had allergic rhinitis, and other allergies. Three patients did not respond to any of the 10 serotypes contained in pneumococcal polysaccharide vaccine, and those who responded were with low titers. Treatment with conjugate pneumococcal vaccine was favorable in 11/12 patients.

Conclusion: In children older than 2 years with recurrent respiratory infections or invasive S. pneumoniae infections with normal immunoglobulin we recommend to investigate SAD, especially if they have a concurrent allergic disease.
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http://dx.doi.org/10.1016/j.rchipe.2016.08.006DOI Listing
April 2017

Low-protein formula slows weight gain in infants of overweight mothers.

J Pediatr Gastroenterol Nutr 2014 Jul;59(1):70-7

*Department of Basic Sciences, Universidad de La Frontera, Temuco, Chile †Nestlé Nutrition Institute, Vevey, Switzerland ‡Nestlé R&D, Nestec Ltd, Vevey, Switzerland §Department of Pediatrics, University of Iowa, Iowa City.

Objectives: Infant formulas provide more protein than breast milk. High protein intakes, as well as maternal obesity, are risk factors for later obesity. The present study tested whether a formula with lower protein content slows weight gain of infants of overweight mothers (body mass index [BMI] >25 kg/m).

Methods: In a randomized double-blind study infants of overweight mothers received from 3 months an experimental (EXPL) formula with 1.65 g of protein/100 kcal (62.8 kcal/100 mL) and containing probiotics, or a control (CTRL) formula with 2.7 g of protein/100 kcal (65.6 kcal/100 mL). Breast-fed infants were studied concurrently. Primary assessment was between 3 and 6 months, although formulas were fed until 12 months. Biomarkers of protein metabolism (blood urea nitrogen, insulin growth factor-1, insulinogenic amino acids) were measured.

Results: Infants fed the low-protein EXPL formula gained less weight between 3 and 6 months (-1.77 g/day, P=0.024) than infants fed the CTRL formula. In the subgroup of infants of mothers with BMI>30 kg/m the difference was -4.21 g/day (P=0.017). Weight (P=0.011) and BMI (P=0.027) of EXPL infants remained lower than that of CTRL infants until 2 years but were similar to that of breast-fed infants. Blood urea nitrogen, insulin growth factor-1, and insulinogenic amino acids at 6 months were significantly lower in EXPL compared with CTRL.

Conclusions: A low-protein formula with probiotics slowed weight gain between 3 and 6 months in infants of overweight mothers. Weight gain and biomarkers were more like those of breast-fed infants.
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http://dx.doi.org/10.1097/MPG.0000000000000349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4086775PMC
July 2014

Impact of breast-feeding and high- and low-protein formula on the metabolism and growth of infants from overweight and obese mothers.

Pediatr Res 2014 Apr 27;75(4):535-43. Epub 2013 Dec 27.

Nestec, Clinical Development Unit, Lausanne, Switzerland.

Background: The combination of maternal obesity in early pregnancy and high protein intake in infant formula feeding might predispose to obesity risk in later life.

Methods: This study assesses the impact of breast- or formula-feeding (differing in protein content by 1.65 or 2.7 g/100 kcal) on the metabolism of term infants from overweight and obese mothers. From birth to 3 mo of age, infants received exclusively either breast- or starter formula-feeding and until 6 mo, exclusively either a formula designed for this study or breast-feeding. From 6 to 12 mo, infants received complementary weaning food. Metabonomics was conducted on the infants' urine and stool samples collected at the age of 3, 6, and 12 mo.

Results: Infant formula-feeding resulted in higher protein-derived short-chain fatty acids and amino acids in stools. Urine metabonomics revealed a relationship between bacterial processing of dietary proteins and host protein metabolism stimulated with increasing protein content in the formula. Moreover, formula-fed infants were metabolically different from breast-fed infants, at the level of lipid and energy metabolism (carnitines, ketone bodies, and Krebs cycle).

Conclusion: Noninvasive urine and stool metabolic monitoring of responses to early nutrition provides relevant readouts to assess nutritional requirements for infants' growth.
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http://dx.doi.org/10.1038/pr.2013.250DOI Listing
April 2014

Measurement of Haemophilus influenzae type a capsular polysaccharide antibodies in cord blood sera.

Pediatr Infect Dis J 2012 Aug;31(8):876-8

Division of Bacterial Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.

We measured anti-Haemophilus influenzae type a capsular polysaccharide serum immunoglobulin G antibodies in cord blood sera from Mexican (n = 68) and Chilean mothers (n = 72) by enzyme-linked immunosorbent assay. Measurable antibodies were found in 79.3% of samples. Immunoglobulin G antibodies correlated with serum bactericidal activity (r = 0.66). This enzyme-linked immunosorbent assay can be used for the evaluation of adaptive immune responses to Haemophilus influenzae type a and serosurveillance studies in populations at risk.
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http://dx.doi.org/10.1097/INF.0b013e31825ab166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3415859PMC
August 2012

Serological protection induced by Haemophilus influenzae Type B conjugate vaccine in Mexican children: is a booster dose of the vaccine needed?

Clin Vaccine Immunol 2010 Oct 18;17(10):1639-41. Epub 2010 Aug 18.

National Institute of Public Health, Av. Universidad 655, Cuernavaca, Morelos, México.

We determined the seroprevalence of protective antibodies against Hib in Mexican children under the age of five using a standardized enzyme-linked immunosorbent assay. Hib antibodies (≥ 0.15 μg/ml) were present in 95.34% (±1.14% [seroprevalence ± standard error]) of samples. Fewer children aged 30 to 47 months had protective Hib antibody levels (91.45% ± 2.60%) than children from 12 to 29 and 48 to 59 months (97.3% ± 1.34% and 97.44% ± 1.80%, respectively).
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http://dx.doi.org/10.1128/CVI.00249-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2953005PMC
October 2010

Novel mechanism for the generation of human xeno-autoantibodies against the nonhuman sialic acid N-glycolylneuraminic acid.

J Exp Med 2010 Aug 12;207(8):1637-46. Epub 2010 Jul 12.

Department of Medicine, Skaggs School of Pharmacy and PharmaceuticalSciences, University of California, San Diego, La Jolla, CA 92093, USA.

The nonhuman sialic acid N-glycolylneuraminic acid (Neu5Gc) is metabolically incorporated into human tissues from certain mammalian-derived foods, and this occurs in the face of an anti-Neu5Gc "xeno-autoantibody" response. Given evidence that this process contributes to chronic inflammation in some diseases, it is important to understand when and how these antibodies are generated in humans. We show here that human anti-Neu5Gc antibodies appear during infancy and correlate with weaning and exposure to dietary Neu5Gc. However, dietary Neu5Gc alone cannot elicit anti-Neu5Gc antibodies in mice with a humanlike Neu5Gc deficiency. Other postnatally appearing anti-carbohydrate antibodies are likely induced by bacteria expressing these epitopes; however, no microbe is known to synthesize Neu5Gc. Here, we show that trace exogenous Neu5Gc can be incorporated into cell surface lipooligosaccharides (LOS) of nontypeable Haemophilus influenzae (NTHi), a human-specific commensal/pathogen. Indeed, infant anti-Neu5Gc antibodies appear coincident with antibodies against NTHi. Furthermore, NTHi that express Neu5Gc-containing LOS induce anti-Neu5Gc antibodies in Neu5Gc-deficient mice, without added adjuvant. Finally, Neu5Gc from baby food is taken up and expressed by NTHi. As the flora residing in the nasopharynx of infants can be in contact with ingested food, we propose a novel model for how NTHi and dietary Neu5Gc cooperate to generate anti-Neu5Gc antibodies in humans.
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http://dx.doi.org/10.1084/jem.20100575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2916132PMC
August 2010

Immunogenicity of a 23-valent pneumococcal polysaccharide vaccine in elderly residents of a long-term care facility.

Braz J Infect Dis 2007 Jun;11(3):322-6

Medical School of Public Health, University of los Andes, Las Condes, Santiago, Chile.

S. pneumoniae is a significant cause of community-acquired pneumonia in the elderly, and accounts for the majority of the pneumonia deaths among the elderly. We conducted this randomized double-blind study to evaluate the immune response to a 23-valent pneumococcal polysaccharide vaccine and the persistence of antibodies two years after the vaccination in an elderly population in Santiago, Chile. A total of 118 elderly nursing home residents received either the pneumococcal or a tetanus control vaccine. Serum samples were taken at enrollment, at two months, and at two years post-vaccination. Pre-vaccination anti-pneumococcal antibody geometric mean concentrations (GMC) were similar in both study groups, with increased levels of antibodies found only against serotype 14. The pneumococcal vaccine was highly immunogenic at 2 months, and titers remained high two years after the vaccination for the 10 serotypes studied in this elderly population. The results thus support the benefits of this pneumococcal vaccine in this elderly population who are at increased risk of invasive pneumococcal disease.
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http://dx.doi.org/10.1590/s1413-86702007000300005DOI Listing
June 2007

Ten-year surveillance of pneumococcal infections in Temuco, Chile: implications for vaccination strategies.

Clin Vaccine Immunol 2007 Jun 28;14(6):660-4. Epub 2007 Mar 28.

Immunology and Bacteriology Laboratory, Hospital Dr. Hernán Henriquez A, Temuco, Chile.

We monitored Streptococcus pneumoniae serotypes causing invasive infections in patients admitted to one hospital in southern Chile during a 10-year period (1994 to 2004). All specimens isolated from patients with invasive S. pneumoniae infections were serotyped at the CDC in Atlanta, GA. A total of 508 isolates belonged to 58 serotypes. There were 95 infections in patients <2 years old, 33 infections in patients 2 to 4 years old, 61 infections in patients 5 to 14 years old, 66 infections in patients 15 to 44 years old, 134 infections in patients 45 to 64 years old, and 120 infections in patients >or=65 years old. The 10 serotypes isolated with the highest frequency in all groups were, in decreasing order, 1, 3, 14, 5, 19F, 6B, 7F, 12F, 23F, and 6A. The 10 most frequent isolates in children under 2 years of age were 1, 6B, 14, 19F, 5, 23F, 6A, 9V, and 7F. In patients >or=65 years old, the most common serotypes were 3, 7F, 1, 14, 19A, 23F, 19F, 35B, 4, and 5. Penicillin resistance was detected in 14 (2.7%) clinical specimens isolated since 1998, with 13 resistant strains identified since 2001. Vaccine coverage for the 7-valent conjugate vaccine was 42% for children <2 years of age. This study is important for the design of vaccines for this region and to evaluate public health measures to decrease pneumococcal infections.
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http://dx.doi.org/10.1128/CVI.00379-06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1951096PMC
June 2007