Heinz Feldmann

University of Manitoba, Winnipeg, Manitoba, Canada

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Publications (302)1854.6 Total impact

  • Thomas Hoenen, Heinz Feldmann
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    ABSTRACT: Filoviruses cause severe hemorrhagic fevers with case fatality rates of up to 90%, for which no antivirals are currently available. Their categorization as biosafety level 4 agents restricts work with infectious viruses to a few maximum containment laboratories worldwide, which constitutes a significant obstacle for the development of countermeasures. Reverse genetics facilitates the generation of recombinant filoviruses, including reporter-expressing viruses, which have been increasingly used for drug screening and development in recent years. Further, reverse-genetics based lifecycle modeling systems allow modeling of the filovirus lifecycle without the need for a maximum containment laboratory and have recently been optimized for use in high-throughput assays. The availability of these reverse genetics-based tools will significantly improve our ability to find novel antivirals against filoviruses.
    Expert Review of Anti-infective Therapy 08/2014; · 2.07 Impact Factor
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    ABSTRACT: The availability of a robust disease model is essential for the development of countermeasures for Middle East respiratory syndrome coronavirus (MERS-CoV). While a rhesus macaque model of MERS-CoV has been established, the lack of uniform, severe disease in this model complicates the analysis of countermeasure studies. Modeling of the interaction between the MERS-CoV spike glycoprotein and its receptor dipeptidyl peptidase 4 predicted comparable interaction energies in common marmosets and humans. The suitability of the marmoset as a MERS-CoV model was tested by inoculation via combined intratracheal, intranasal, oral and ocular routes. Most of the marmosets developed a progressive severe pneumonia leading to euthanasia of some animals. Extensive lesions were evident in the lungs of all animals necropsied at different time points post inoculation. Some animals were also viremic; high viral loads were detected in the lungs of all infected animals, and total RNAseq demonstrated the induction of immune and inflammatory pathways. This is the first description of a severe, partially lethal, disease model of MERS-CoV, and as such will have a major impact on the ability to assess the efficacy of vaccines and treatment strategies as well as allowing more detailed pathogenesis studies.
    PLoS Pathogens 08/2014; 10(8):e1004250. · 8.14 Impact Factor
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    ABSTRACT: Work with infectious Ebola viruses is restricted to biosafety level (BSL) 4 laboratories, presenting a significant barrier for studying these viruses. Lifecycle modeling systems, including minigenome systems and transcription and replication-competent virus-like particle (trVLP) systems, allow modeling of the virus lifecycle under BSL2 conditions; however, all current systems model only certain aspects of the virus lifecycle, rely on plasmid-based viral protein expression, and have only been used to model single infectious cycles. We have developed a novel lifecycle modeling system allowing continuous passaging of infectious trVLPs containing a tetracistronic minigenome that encodes a reporter and the viral proteins VP40, VP24, and GP1,2. This system is ideally suited for studying morphogenesis, budding and entry, in addition to genome replication and transcription. Importantly, the specific infectivity of trVLPs in this system was ∼500 fold higher than in previous systems. Using this system for functional studies of VP24 we showed that, contrary to previous reports, VP24 only very modestly inhibits genome replication and transcription when expressed in a regulated fashion, which we confirmed using infectious Ebola viruses. Interestingly, we also discovered a genome length-dependent effect of VP24 on particle infectivity, which was previously undetected due to the short length of monocistronic minigenomes, and which is due at least partially to a previously unknown function of VP24 in RNA packaging. Based on our findings we propose a model for the function of VP24 that reconciles all currently available data regarding the role of VP24 in nucleocapsid assembly as well as genome replication and transcription.
    Journal of virology. 06/2014;
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    ABSTRACT: Nipah virus (NiV) is an emerging zoonotic paramyxovirus that causes severe and often fatal disease in pigs and humans. There are currently no vaccines or treatments approved for human use. Studies in small-animal models of NiV infection suggest that antibody therapy may be a promising treatment. However, most studies have assessed treatment at times shortly after virus exposure before animals show signs of disease. We assessed the efficacy of a fully human monoclonal antibody, m102.4, at several time points after virus exposure including at the onset of clinical illness in a uniformly lethal nonhuman primate model of NiV disease. Sixteen African green monkeys (AGMs) were challenged intratracheally with a lethal dose of NiV, and 12 animals were infused twice with m102.4 (15 mg/kg) beginning at either 1, 3, or 5 days after virus challenge and again about 2 days later. The presence of viral RNA, infectious virus, and/or NiV-specific immune responses demonstrated that all subjects were infected after challenge. All 12 AGMs that received m102.4 survived infection, whereas the untreated control subjects succumbed to disease between days 8 and 10 after infection. AGMs in the day 5 treatment group exhibited clinical signs of disease, but all animals recovered by day 16. These results represent the successful therapeutic in vivo efficacy by an investigational drug against NiV in a nonhuman primate and highlight the potential impact that a monoclonal antibody can have on a highly pathogenic zoonotic human disease.
    Science translational medicine 06/2014; 6(242):242ra82. · 10.76 Impact Factor
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    ABSTRACT: Ebola virus (EBOV) causes a severe hemorrhagic disease in humans and nonhuman primates with a median case fatality rate of 78.4%. Although EBOV is considered a public-health concern there is a relative paucity of information regarding the modulation of the functional host response during infection. We employed temporal kinome analysis to investigate the relative early, intermediate, and late host kinome responses to EBOV infection in human hepatocytes. Pathway over-representation analysis and functional network analysis of kinome data revealed that transforming growth factor (TGF)-β-mediated signaling responses were temporally modulated in response to EBOV infection. Up-regulation of TGF-β signaling in the kinome data sets correlated with the up-regulation of TGF-β secretion from EBOV infected cells. Kinase inhibitors targeting TGF-β signaling, or additional cell receptors and downstream signaling pathway intermediates identified from our kinome analysis, also inhibited EBOV replication. Further, the inhibition of select cell signaling intermediates identified from our kinome analysis provided partial protection in a lethal model of EBOV infection. To gain perspective on the cellular consequence of TGF-β signaling modulation during EBOV infection we assessed cellular markers associated with up-regulation of TGF-β signaling. We observed up-regulation of matrix metalloproteinase 9, N-cadherin, and fibronectin expression with concomitant reductions in the expression of E-cadherin and claudin-1, responses that are standard characteristics of epithelial to mesenchymal -like transition. Additionally, we identified phosphorylation events downstream of TGF-β that may contribute to this process. From these observations we propose a model for a broader role of TGF-β-mediated signaling responses in the pathogenesis of Ebola virus disease.
    Journal of virology. 06/2014;
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    ABSTRACT: Although lymphopenia is a hallmark of severe infection with highly pathogenic H5N1 and the newly emerged H7N9 influenza viruses in humans, the mechanism(s) by which lethal H5N1 viruses cause lymphopenia in mammalian hosts remains poorly understood. Because influenza-specific T cell responses are initiated in the lung draining lymph nodes (LNs), and lymphocytes subsequently traffic to the lungs or peripheral circulation, we compared the immune responses in the lung draining LNs postinfection with a lethal A/HK/483/97 or nonlethal A/HK/486/97 (H5N1) virus in a mouse model. We found that lethal H5N1, but not nonlethal H5N1, virus infection in mice enhances Fas ligand (FasL) expression on plasmacytoid dendritic cells (pDCs), resulting in apoptosis of influenza-specific CD8(+) T cells via a Fas-FasL-mediated pathway. We also found that pDCs, but not other DC subsets, preferentially accumulate in the lung draining LNs of lethal H5N1 virus-infected mice, and that the induction of FasL expression on pDCs correlates with high levels of IL-12p40 monomer/homodimer in the lung draining LNs. Our data suggest that one of the mechanisms of lymphopenia associated with lethal H5N1 virus infection involves a deleterious role for pDCs.
    The Journal of Immunology 05/2014; · 5.52 Impact Factor
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    ABSTRACT: Hantavirus cardiopulmonary syndrome (HCPS) is a rodent-borne disease with a high case-fatality rate that is caused by several New World hantaviruses. Each pathogenic hantavirus is naturally hosted by a principal rodent species without conspicuous disease and infection is persistent, perhaps for life. Deer mice (Peromyscus maniculatus) are the natural reservoirs of Sin Nombre virus (SNV), the etiologic agent of most HCPS cases in North America. Deer mice remain infected despite a helper T cell response that leads to high titer neutralizing antibodies. Deer mice are also susceptible to Andes hantavirus (ANDV), which causes most HCPS cases in South America; however, deer mice clear ANDV. We infected deer mice with SNV or ANDV to identify differences in host responses that might account for this differential outcome. SNV RNA levels were higher in the lungs but not different in heart, spleen or kidney. Most ANDV-infected deer mice had seroconverted 14 days after inoculation but none of the SNV-infected deer mice had. Examination of lymph node cell antigen recall responses identified elevated immune gene expression in deer mice infected with ANDV and suggested maturation towards a Th2 or T follicular helper phenotype in some ANDV-infected deer mice, including activation of the IL-4 pathway in T cells and B cells. These data suggest the rate of maturation of the immune response is substantially faster and of greater magnitude during ANDV infection, and these differences may account for clearance of ANDV and persistence of SNV. Hantaviruses persistently infect their reservoir rodent hosts without pathology. It is unknown how these viruses evade sterilizing immune responses in the reservoirs. We have determined that infection of the deer mouse with its homologous hantavirus, Sin Nombre virus, results in low levels of immune gene expression in antigen-stimulated lymph node cells and a poor antibody response. However, infection of deer mice with a heterologous hantavirus, Andes virus, results in a robust lymph node cell response, signatures of T and B cell maturation, and production of antibodies. These findings suggest that an early and aggressive immune response to hantaviruses may lead to clearance in a reservoir host and suggests that a modest immune response may be a component of hantavirus ecology.
    Journal of Virology 05/2014; · 5.08 Impact Factor
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    ABSTRACT: Live attenuated cold adapted (ca) H5N1, H7N3, H6N1 and H9N2 influenza vaccine viruses replicated in the respiratory tract of mice and ferrets and 2 doses of vaccines were immunogenic and protected these animals from challenge infection with homologous and heterologous wild type (wt) viruses of the corresponding subtypes. However, when these vaccine candidates were evaluated in Phase I clinical trials, there were inconsistencies between the observations in animal models and humans. The vaccine viruses did not replicate well and immune responses were variable in humans, even though the study subjects were seronegative to the vaccine viruses before vaccination. Therefore, we sought a model that would better reflect the findings in humans and evaluated African green monkeys (AGMs) as a non-human primate model. The distribution of sialic acid (SA) receptors in the respiratory tract of AGMs was similar to humans. We evaluated the replication of wt and ca viruses of avian influenza (AI) subtypes, H5N1, H6N1, H7N3, and H9N2 in the respiratory tract of AGMs. All of the wt viruses replicated efficiently while replication of the ca vaccine viruses was restricted to the upper respiratory tract. Interestingly, the pattern and site of virus replication differed among the different subtypes. We also evaluated the immunogenicity and protective efficacy of H5N1, H6N1, H7N3 and H9N2 ca vaccines. Protection from wt virus challenge correlated well with the level of serum neutralizing antibodies. Immune responses were slightly better when vaccine was delivered by both intranasal and intratracheal delivery than intranasally by sprayer. We conclude that live attenuated pandemic influenza virus vaccines replicate similarly in AGMs and human subjects, and that AGMs may be useful model to evaluate the replication of ca vaccine candidates. Ferrets and mice are commonly used for preclinical evaluation of influenza vaccines. However, we experienced significant inconsistencies between observations in humans and in these animal models. We used African green monkeys (AGMs) as a non-human primate (NHP) model for a comprehensive and comparative evaluation of pairs of wild-type and pandemic live attenuated influenza vaccines (pLAIV) representing four subtypes of avian influenza viruses and found that pLAIVs replicate similarly in AGMs and humans, and that AGMs can be useful for evaluation of the protective efficacy of pLAIV.
    Journal of Virology 05/2014; · 5.08 Impact Factor
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    Emerging Infectious Diseases 05/2014; 20(5):911-3. · 6.79 Impact Factor
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    ABSTRACT: The pathophysiology of hantavirus pulmonary syndrome (HPS) remains unclear because of a lack of surrogate disease models with which to perform pathogenesis studies. Nonhuman primates (NHP) are considered the gold standard model for studying the underlying immune activation/suppression associated with immunopathogenic viruses such as hantaviruses; however, to date an NHP model for HPS has not been described. Here we show that rhesus macaques infected with Sin Nombre virus (SNV), the primary etiological agent of HPS in North America, propagated in deer mice develop HPS, which is characterized by thrombocytopenia, leukocytosis, and rapid onset of respiratory distress caused by severe interstitial pneumonia. Despite establishing a systemic infection, SNV differentially activated host responses exclusively in the pulmonary endothelium, potentially the mechanism leading to acute severe respiratory distress. This study presents a unique chronological characterization of SNV infection and provides mechanistic data into the pathophysiology of HPS in a closely related surrogate animal model. We anticipate this model will advance our understanding of HPS pathogenesis and will greatly facilitate research toward the development of effective therapeutics and vaccines against hantaviral diseases.
    Proceedings of the National Academy of Sciences 04/2014; · 9.81 Impact Factor
  • Darryl Falzarano, Heinz Feldmann
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    ABSTRACT: In a recent study published in Nature, Warren et al. describe the generation of a novel synthetic adenosine analogue, BCX4430, a synthetic drug-like small molecule that provides protection from Ebola and Marburg virus infection in animal models.
    Cell Research 04/2014; · 10.53 Impact Factor
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    ABSTRACT: Seoul virus, an Old World hantavirus, is maintained in brown rats and causes a mild form of hemorrhagic fever with renal syndrome (HFRS) in humans. We captured rodents in New Orleans, Louisiana and tested them for the presence of Old World hantaviruses by reverse transcription polymerase chain reaction (RT-PCR) with sequencing, cell culture, and electron microscopy; 6 (3.4%) of 178 rodents captured-all brown rats-were positive for a Seoul virus variant previously coined Tchoupitoulas virus, which was noted in rodents in New Orleans in the 1980s. The finding of Tchoupitoulas virus in New Orleans over 25 years since its first discovery suggests stable endemicity in the city. Although the degree to which this virus causes human infection and disease remains unknown, repeated demonstration of Seoul virus in rodent populations, recent cases of laboratory-confirmed HFRS in some US cities, and a possible link with hypertensive renal disease warrant additional investigation in both rodents and humans.
    The American journal of tropical medicine and hygiene 03/2014; · 2.53 Impact Factor
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    ABSTRACT: Nipah virus (NiV), a zoonotic pathogen causing severe respiratory illness and encephalitis in humans, emerged in Malaysia in 1998 with subsequent outbreaks on an almost annual basis since 2001 in parts of the Indian subcontinent. The high case fatality rate, human-to-human transmission, wide-ranging reservoir distribution and lack of licensed intervention options are making NiV a serious regional and potential global public health problem. The objective of this study was to develop a fast-acting, single-dose NiV vaccine that could be implemented in a ring vaccination approach during outbreaks. In this study we have designed new live-attenuated vaccine vectors based on recombinant vesicular stomatitis viruses (rVSV) expressing NiV glycoproteins (G or F) or nucleoprotein (N) and evaluated their protective efficacy in Syrian hamsters, an established NiV animal disease model. We further characterized the humoral immune response to vaccination in hamsters using ELISA and neutralization assays and performed serum transfer studies. Vaccination of Syrian hamsters with a single dose of the rVSV vaccine vectors resulted in strong humoral immune responses with neutralizing activities found only in those animals vaccinated with rVSV expressing NiV G or F proteins. Vaccinated animals with neutralizing antibody responses were completely protected from lethal NiV disease, whereas animals vaccinated with rVSV expressing NiV N showed only partial protection. Protection of NiV G or F vaccinated animals was conferred by antibodies, most likely the neutralizing fraction, as demonstrated by serum transfer studies. Protection of N-vaccinated hamsters was not antibody-dependent indicating a role of adaptive cellular responses for protection. The rVSV vectors expressing Nipah virus G or F are prime candidates for new 'emergency vaccines' to be utilized for NiV outbreak management.
    Vaccine 03/2014; · 3.77 Impact Factor
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    ABSTRACT: Since 2001, outbreaks of Nipah virus have occurred almost every year in Bangladesh with high case-fatality rates. Epidemiological data suggest that in Bangladesh, Nipah virus is transmitted from the natural reservoir, fruit bats, to humans via consumption of date palm sap contaminated by bats, with subsequent human-to-human transmission. To experimentally investigate this epidemiological association between drinking of date palm sap and human cases of Nipah virus infection, we determined the viability of Nipah virus (strain Bangladesh/200401066) in artificial palm sap. At 22°C virus titers remained stable for at least 7 days, thus potentially allowing food-borne transmission. Next, we modeled food-borne Nipah virus infection by supplying Syrian hamsters with artificial palm sap containing Nipah virus. Drinking of 5×108 TCID50 of Nipah virus resulted in neurological disease in 5 out of 8 hamsters, indicating that food-borne transmission of Nipah virus can indeed occur. In comparison, intranasal (i.n.) inoculation with the same dose of Nipah virus resulted in lethal respiratory disease in all animals. In animals infected with Nipah virus via drinking, virus was detected in respiratory tissues rather than in the intestinal tract. Using fluorescently labeled Nipah virus particles, we showed that during drinking, a substantial amount of virus is deposited in the lungs, explaining the replication of Nipah virus in the respiratory tract of these hamsters. Besides the ability of Nipah virus to infect hamsters via the drinking route, Syrian hamsters infected via that route transmitted the virus through direct contact with naïve hamsters in 2 out of 24 transmission pairs. Although these findings do not directly prove that date palm sap contaminated with Nipah virus by bats is the origin of Nipah virus outbreaks in Bangladesh, they provide the first experimental support for this hypothesis. Understanding the Nipah virus transmission cycle is essential for preventing and mitigating future outbreaks.
    PLoS Pathogens 03/2014; 10(3):e1004001. · 8.14 Impact Factor
  • Andrea Marzi, Heinz Feldmann
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    ABSTRACT: Ebola hemorrhagic fever is one of the most fatal viral diseases worldwide affecting humans and nonhuman primates. Although infections only occur frequently in Central Africa, the virus has the potential to spread globally and is classified as a category A pathogen that could be misused as a bioterrorism agent. As of today there is no vaccine or treatment licensed to counteract Ebola virus infections. DNA, subunit and several viral vector approaches, replicating and non-replicating, have been tested as potential vaccine platforms and their protective efficacy has been evaluated in nonhuman primate models for Ebola virus infections, which closely resemble disease progression in humans. Though these vaccine platforms seem to confer protection through different mechanisms, several of them are efficacious against lethal disease in nonhuman primates attesting that vaccination against Ebola virus infections is feasible.
    Expert Review of Vaccines 02/2014; · 4.22 Impact Factor
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    ABSTRACT: Andes virus (ANDV) is highly pathogenic in humans and is the primary etiologic agent of hantavirus cardiopulmonary syndrome (HCPS) in South America. Case-fatality rates are as high as 50% and there are no approved vaccines or specific therapies for infection. Our laboratory has recently developed a replication-competent recombinant vesicular stomatitis virus (VSV)-based vaccine that expressed the glycoproteins of Andes virus in place of the native VSV glycoprotein (G). This vaccine is highly efficacious in the Syrian hamster model of HCPS when given 28 days before challenge with ANDV, or when given around the time of challenge (peri-exposure), and even protects when administered post-exposure. Herein, we sought to test the durability of the immune response to a single dose of this vaccine in Syrian hamsters. This vaccine was efficacious in hamsters challenged intranasally with ANDV 6 months after vaccination (p = 0.025), but animals were not significantly protected following 1 year of vaccination (p = 0.090). The decrease in protection correlated with a reduction of measurable neutralizing antibody responses, and suggests that a more robust vaccination schedule might be required to provide long-term immunity.
    Viruses 01/2014; 6(2):516-23. · 2.51 Impact Factor
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    ABSTRACT: The filoviruses, Marburg virus (MARV) and Ebola virus, causes severe hemorrhagic fever with high mortality in humans and nonhuman primates. A promising filovirus vaccine under development is based on a recombinant vesicular stomatitis virus (rVSV) that expresses individual filovirus glycoproteins (GPs) in place of the VSV glycoprotein (G). These vaccines have shown 100% efficacy against filovirus infection in nonhuman primates when challenge occurs 28-35 days after a single injection immunization. Here, we examined the ability of a rVSV MARV-GP vaccine to provide protection when challenge occurs more than a year after vaccination. Cynomolgus macaques were immunized with rVSV-MARV-GP and challenged with MARV approximately 14 months after vaccination. Immunization resulted in the vaccine cohort of six animals having anti-MARV GP IgG throughout the pre-challenge period. Following MARV challenge none of the vaccinated animals showed any signs of clinical disease or viremia and all were completely protected from MARV infection. Two unvaccinated control animals exhibited signs consistent with MARV infection and both succumbed. Importantly, these data are the first to show 100% protective efficacy against any high dose filovirus challenge beyond 8 weeks after final vaccination. These findings demonstrate the durability of VSV-based filovirus vaccines.
    PLoS ONE 01/2014; 9(4):e94355. · 3.53 Impact Factor
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    ABSTRACT: Filoviruses are the causative agents of lethal hemorrhagic fever in human and non-human primates (NHP). The family of Filoviridae is composed of three genera, Ebolavirus, Marburgvirus and Cuevavirus. There are currently no approved vaccines or antiviral therapeutics for the treatment of filovirus infections in humans. Passive transfer of neutralizing antibodies targeting the Ebola virus (EBOV) glycoprotein (GP) has proven effective in protecting mice, guinea pigs and NHP from lethal challenges with EBOV. In this study, we generated two neutralizing monoclonal antibodies (MAbs), termed S9 and M4 that recognize the GP of EBOV or multiple strains of Marburg virus (MARV), respectively. We characterized the putative binding site of S9 as a linear epitope on the glycan cap of the GP1 subunit of the EBOV-GP. The M4 antibody recognizes an unknown conformational epitope on MARV-GP. Additionally, we demonstrated the post-exposure protection potential of these antibodies in both the mouse and guinea pig models of filovirus infection. These data indicate that MAbs S9 and M4 would be good candidates for inclusion in an antibody cocktail for the treatment of filovirus infections.
    Trials in Vaccinology. 01/2014; 3:89–94.
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    ABSTRACT: Ebolavirus (EBOV), the causative agent of a severe hemorrhagic fever and a biosafety level 4 pathogen, increases its genome coding capacity by producing multiple transcripts encoding for structural and nonstructural glycoproteins from a single gene. This is achieved through RNA editing, during which non-template adenosine residues are incorporated into the EBOV mRNAs at an editing site encoding for 7 adenosine residues. However, the mechanism of EBOV RNA editing is currently not understood. In this study, we report for the first time that minigenomes containing the glycoprotein gene editing site can undergo RNA editing, thereby eliminating the requirement for a biosafety level 4 laboratory to study EBOV RNA editing. Using a newly developed dual-reporter minigenome, we have characterized the mechanism of EBOV RNA editing, and have identified cis-acting sequences that are required for editing, located between 9 nt upstream and 9 nt downstream of the editing site. Moreover, we show that a secondary structure in the upstream cis-acting sequence plays an important role in RNA editing. EBOV RNA editing is glycoprotein gene-specific, as a stretch encoding for 7 adenosine residues located in the viral polymerase gene did not serve as an editing site, most likely due to an absence of the necessary cis-acting sequences. Finally, the EBOV protein VP30 was identified as a trans-acting factor for RNA editing, constituting a novel function for this protein. Overall, our results provide novel insights into the RNA editing mechanism of EBOV, further understanding of which might result in novel intervention strategies against this viral pathogen. This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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    ABSTRACT: Staphylococcus aureus community-acquired pneumonia is often associated with influenza or an influenza-like syndrome. Morbidity and mortality due to methicillin-resistant S. aureus (MRSA) or influenza and pneumonia, which includes bacterial co-infection, are among the top causes of death by infectious diseases in the United States. We developed a non-lethal IAV (H3N2)/S. aureus co-infection model in cynomolgus macaques (Macaca fascicularis) to test the hypothesis that seasonal influenza A virus (IAV) infection predisposes non-human primates to severe S. aureus pneumonia. Infection and disease progression were monitored by clinical assessment of animal health; analysis of blood chemistry, nasal swabs, and X-rays; and gross pathology and histopathology of lungs from infected animals. Seasonal IAV infection in healthy cynomolgus macaques caused mild pneumonia, but unexpectedly, did not predispose these animals to subsequent severe infection with the community-associated MRSA clone USA300. We conclude that in our co-infection model, seasonal IAV infection alone is not sufficient to promote severe S. aureus pneumonia in otherwise healthy non-human primates. The implication of these findings is that comorbidity factors in addition to IAV infection are required to predispose individuals to secondary S. aureus pneumonia.
    Virulence 10/2013; 4(8). · 2.79 Impact Factor

Publication Stats

9k Citations
1,854.60 Total Impact Points


  • 2003–2014
    • University of Manitoba
      Winnipeg, Manitoba, Canada
  • 1994–2014
    • National Institute of Allergy and Infectious Diseases
      • Laboratory of Immunoregulation
      Maryland, United States
  • 2013
    • University of California, Davis
      Davis, California, United States
  • 2012–2013
    • National Institute of Allergy and Infectious Disease
      Hamilton, Ohio, United States
    • Erasmus MC
      • Department of Virology
      Rotterdam, South Holland, Netherlands
  • 2011–2013
    • University of Zambia
      • School of Veterinary Medicine
      Lusaka, Lusaka Province, Zambia
    • Hannover Medical School
      • Institute of Virology
      Hannover, Lower Saxony, Germany
    • Benaroya Research Institute
      Seattle, Washington, United States
    • University of Washington Seattle
      • Department of Microbiology
      Seattle, WA, United States
  • 2010–2013
    • National Institutes of Health
      • Laboratory of Virology (LV)
      Bethesda, MD, United States
    • National Institute of Infectious Diseases, Tokyo
      Edo, Tōkyō, Japan
  • 2002–2013
    • National Microbiology Laboratory, Canada
      Winnipeg, Manitoba, Canada
  • 2011–2012
    • Boston University
      • Department of Microbiology
      Boston, MA, United States
  • 2009–2012
    • Kansas State University
      • College of Veterinary Medicine
      Kansas, United States
  • 2005–2012
    • University of Texas Medical Branch at Galveston
      • • Department of Microbiology and Immunology
      • • Department of Pathology
      Galveston, Texas, United States
    • Public Health Agency of Canada
      • Special Pathogens Program
      Ottawa, Ontario, Canada
    • United States Army Medical Research Institute for Infectious Diseases
      Maryland, United States
  • 2003–2012
    • The University of Tokyo
      • • Department of Microbiology and Immunology
      • • Institute of Medical Science
      • • International Research Center for Infectious Diseases
      Edo, Tōkyō, Japan
  • 1988–2012
    • Philipps-Universität Marburg
      • Institut für Virologie
      Marburg, Hesse, Germany
  • 2007–2011
    • National Institute of Police Science Japan
      Tiba, Chiba, Japan
  • 2003–2011
    • Technische Universität Dresden
      • Institut für Physiologie
      Dresden, Saxony, Germany
  • 2002–2011
    • University of Wisconsin, Madison
      • Department of Pathobiological Sciences
      Mississippi, United States
  • 1998–2011
    • University of Münster
      • • Institute of Zoophysiology (Hospital)
      • • Institute of Physiology
      Muenster, North Rhine-Westphalia, Germany
  • 2001–2010
    • Robert Koch Institut
      Berlín, Berlin, Germany
    • Carl Gustav Carus-Institut
      Pforzheim, Baden-Württemberg, Germany
  • 2008
    • University of Texas at Austin
      • Division of Pharmaceutics
      Texas City, TX, United States
  • 2006–2007
    • Hokkaido University
      • • Research Center for Zoonosis Control
      • • Laboratory of Microbiology
      Sapporo-shi, Hokkaido, Japan
    • Columbia University
      • Center for Infection and Immunity
      New York City, NY, United States
    • Hospital of the University of Pennsylvania
      • Department of Pathology and Laboratory Medicine
      Philadelphia, PA, United States
    • U.S. Army Medical Research Institute of Infectious Diseases
      Maryland, United States
    • The University of Winnipeg
      Winnipeg, Manitoba, Canada
  • 2004
    • Southern Research Institute
      Birmingham, Alabama, United States
    • Ludwig Institute for Cancer Research Sweden
      Uppsala, Uppsala, Sweden
  • 2003–2004
    • Bundeswehr Institute of Microbiology
      München, Bavaria, Germany
  • 2002–2004
    • Health Canada
      • Canadian Science Centre for Human and Animal Health
      Ottawa, Ontario, Canada
  • 1993–1999
    • Centers for Disease Control and Prevention
      • National Center for Emerging and Zoonotic Infectious Diseases
      Atlanta, Michigan, United States
  • 1995
    • Heinrich-Heine-Universität Düsseldorf
      Düsseldorf, North Rhine-Westphalia, Germany
  • 1992
    • Georgia State University
      • Department of Biology
      Atlanta, GA, United States