Publications by authors named "Joshua M Klonoski"

6 Publications

  • Page 1 of 1

A Novel Role for PDZ-Binding Motif of Influenza A Virus Nonstructural Protein 1 in Regulation of Host Susceptibility to Postinfluenza Bacterial Superinfections.

Viral Immunol 2019 04 1;32(3):131-143. Epub 2019 Mar 1.

1 Department of Microbiology and Immunology, Montana State University, Bozeman, Montana.

Influenza A viruses (IAVs) have multiple mechanisms for altering the host immune response to aid in virus survival and propagation. While both type I and II interferons (IFNs) have been associated with increased bacterial superinfection (BSI) susceptibility, we found that in some cases type I IFNs can be beneficial for BSI outcome. Specifically, we have shown that antagonism of the type I IFN response during infection by some IAVs can lead to the development of deadly BSI. The nonstructural protein 1 (NS1) from IAV is well known for manipulating host type I IFN responses, but the viral proteins mediating BSI severity remain unknown. In this study, we demonstrate that the PDZ-binding motif (PDZ-bm) of the NS1 C-terminal region from mouse-adapted A/Puerto Rico/8/34-H1N1 (PR8) IAV dictates BSI susceptibility through regulation of IFN-α/β production. Deletion of the NS1 PDZ-bm from PR8 IAV (PR8-TRUNC) resulted in 100% survival and decreased bacterial burden in superinfected mice compared with 0% survival in mice superinfected after PR8 infection. This reduction in BSI susceptibility after infection with PR8-TRUNC was due to the presence of IFN-β, as protection from BSI was lost in Ifn-β mice, resembling BSI during PR8 infection. PDZ-bm in PR8-infected mice inhibited the production of IFN-β posttranscriptionally, and both delayed and reduced expression of the tunable interferon-stimulated genes. Finally, a similar lack of BSI susceptibility, due to the presence of IFN-β on day 7 post-IAV infection, was also observed after infection of mice with A/TX98-H3N2 virus that naturally lacks a PDZ-bm in NS1, indicating that this mechanism of BSI regulation by NS1 PDZ-bm may not be restricted to PR8 IAV. These results demonstrate that the NS1 C-terminal PDZ-bm, like the one present in PR8 IAV, is involved in controlling susceptibility to BSI through the regulation of IFN-β, providing new mechanisms for NS1-mediated manipulation of host immunity and BSI severity.
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http://dx.doi.org/10.1089/vim.2018.0118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6479245PMC
April 2019

Contributions of Influenza Virus Hemagglutinin and Host Immune Responses Toward the Severity of Influenza Virus: Streptococcus pyogenes Superinfections.

Viral Immunol 2018 Jul/Aug;31(6):457-469. Epub 2018 Jun 5.

1 Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota , Vermillion, South Dakota.

Influenza virus infections can be complicated by bacterial superinfections, which are medically relevant because of a complex interaction between the host, the virus, and the bacteria. Studies to date have implicated several influenza virus genes, varied host immune responses, and bacterial virulence factors, however, the host-pathogen interactions that predict survival versus lethal outcomes remain undefined. Previous work by our group showed that certain influenza viruses could yield a survival phenotype (A/swine/Texas/4199-2/98-H3N2, TX98), whereas others were associated with a lethal phenotype (A/Puerto Rico/8/34-H1N1, PR8). Based on this observation, we developed the hypothesis that individual influenza virus genes could contribute to a superinfection, and that the host response after influenza virus infection could influence superinfection severity. The present study analyzes individual influenza virus gene contributions to superinfection severity using reassortant viruses created using TX98 and PR8 viral genes. Host and pathogen interactions, relevant to survival and lethal phenotypes, were studied with a focus on pathogen clearance, host cellular infiltrates, and cytokine levels after infection. Specifically, we found that the hemagglutinin gene expressed by an influenza virus can contribute to the severity of a secondary bacterial infection, likely through modulation of host proinflammatory responses. Altogether, these results advance our understanding of molecular mechanisms underlying influenza virus-bacteria superinfections and identify viral and corresponding host factors that may contribute to morbidity and mortality.
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http://dx.doi.org/10.1089/vim.2017.0193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043403PMC
October 2018

Vaccination against the M protein of Streptococcus pyogenes prevents death after influenza virus: S. pyogenes super-infection.

Vaccine 2014 Sep 29;32(40):5241-9. Epub 2014 Jul 29.

Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD, United States. Electronic address:

Influenza virus infections are associated with a significant number of illnesses and deaths on an annual basis. Many of the deaths are due to complications from secondary bacterial invaders, including Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, and Streptococcus pyogenes. The β-hemolytic bacteria S. pyogenes colonizes both skin and respiratory surfaces, and frequently presents clinically as strep throat or impetigo. However, when these bacteria gain access to normally sterile sites, they can cause deadly diseases including sepsis, necrotizing fasciitis, and pneumonia. We previously developed a model of influenza virus:S. pyogenes super-infection, which we used to demonstrate that vaccination against influenza virus can limit deaths associated with a secondary bacterial infection, but this protection was not complete. In the current study, we evaluated the efficacy of a vaccine that targets the M protein of S. pyogenes to determine whether immunity toward the bacteria alone would allow the host to survive an influenza virus:S. pyogenes super-infection. Our data demonstrate that vaccination against the M protein induces IgG antibodies, in particular those of the IgG1 and IgG2a isotypes, and that these antibodies can interact with macrophages. Ultimately, this vaccine-induced immunity eliminated death within our influenza virus:S. pyogenes super-infection model, despite the fact that all M protein-vaccinated mice showed signs of illness following influenza virus inoculation. These findings identify immunity against bacteria as an important component of protection against influenza virus:bacteria super-infection.
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http://dx.doi.org/10.1016/j.vaccine.2014.06.093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4146501PMC
September 2014

Enhanced response to pulmonary Streptococcus pneumoniae infection is associated with primary ciliary dyskinesia in mice lacking Pcdp1 and Spef2.

Cilia 2013 Dec 20;2(1):18. Epub 2013 Dec 20.

Sanford Children's Health Research Center, Sanford Research/USD, 2301 E, 60th St, N, Sioux Falls, SD 57104, USA.

Background: Lower airway abnormalities are common in patients with primary ciliary dyskinesia (PCD), a pediatric syndrome that results from structural or functional defects in motile cilia. Patients can suffer from recurrent bacterial infection in the lung, bronchiectasis, and respiratory distress in addition to chronic sinusitis, otitis media, infertility, and laterality defects. However, surprisingly little is known about the pulmonary phenotype of mouse models of this disorder.

Results: The pulmonary phenotype of two mouse models of PCD, nm1054 and bgh, which lack Pcdp1 and Spef2, respectively, was investigated by histological and immunohistochemical analysis. In addition, both models were challenged with Streptococcus pneumoniae, a common respiratory pathogen found in the lungs of PCD patients. Histopathological analyses reveal no detectable cellular, developmental, or inflammatory abnormalities in the lower airway of either PCD model. However, exposure to S. pneumoniae results in a markedly enhanced inflammatory response in both models. Based on analysis of inflammatory cells in bronchoalveolar lavage fluid and flow cytometric analysis of cytokines in the lung, the bgh model shows a particularly dramatic lymphocytic response by 3 days post-infection compared to the nm1054 model or wild type animals.

Conclusions: Defects in ciliary motility result in a severe response to pulmonary infection. The PCD models nm1054 and bgh are distinct and clinically relevant models for future studies investigating the role of mucociliary clearance in host defense.
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http://dx.doi.org/10.1186/2046-2530-2-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3878133PMC
December 2013

Contribution of murine innate serum inhibitors toward interference within influenza virus immune assays.

Influenza Other Respir Viruses 2012 Mar 29;6(2):127-35. Epub 2011 Aug 29.

Division of Basic Biomedical Sciences, University of South Dakota, Vermillion, SD 57069-2390, USA.

Background: Prior to detection of an antibody response toward influenza viruses using the hemagglutination inhibition assay (HAI), sera are routinely treated to inactivate innate inhibitors using both heat inactivation (56°C) and recombinant neuraminidase [receptor-destroying enzyme (RDE)].

Objectives: We revisited the contributions of innate serum inhibitors toward interference with influenza viruses in immune assays, using murine sera, with emphasis on the interactions with influenza A viruses of the H3N2 subtype.

Methods: We used individual serum treatments: 56°C alone, RDE alone, or RDE + 56°C, to treat sera prior to evaluation within HAI, microneutralization, and macrophage uptake assays.

Results: Our data demonstrate that inhibitors present within untreated murine sera interfere with the HAI assay in a manner that is different from that seen for the microneutralization assay. Specifically, the γ class inhibitor α(2) -Macroglobulin (A2-M) can inhibit H3N2 viruses within the HAI assay, but not in the microneutralization assay. Based on these findings, we used a macrophage uptake assay to demonstrate that these inhibitors can increase uptake by macrophages when the influenza viruses express an HA from a 1968 H3N2 virus isolate, but not a 1997 H3N2 isolate.

Conclusions: The practice of treating sera to inactivate innate inhibitors of influenza viruses prior to evaluation within immune assays has allowed us to effectively detect influenza virus-specific antibodies for decades. However, this practice has yielded an under-appreciation for the contribution of innate serum inhibitors toward host immune responses against these viruses, including contributions toward neutralization and macrophage uptake.
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http://dx.doi.org/10.1111/j.1750-2659.2011.00283.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3235232PMC
March 2012

In vitro chromatin self-association and its relevance to genome architecture.

Biochem Cell Biol 2006 Aug;84(4):411-7

Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523-1870, USA.

Chromatin in a eukaryotic nucleus is condensed through 3 hierarchies: primary, secondary, and tertiary chromatin structures. In vitro, when induced with cations, chromatin can self-associate and form large oligomers. This self-association process has been proposed to mimic processes involved in the assembly and maintenance of tertiary chromatin structures in vivo. In this article, we review 30 years of studies of chromatin self-association, with an emphasis on the evidence suggesting that this in vitro process is physiologically relevant.
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http://dx.doi.org/10.1139/o06-068DOI Listing
August 2006
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