scholarly journals Platelets Can Phagocytose Influenza Virus Which May Contribute to the Occurrence of Thrombocytopenia during Influenza Infection

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1358-1358 ◽  
Author(s):  
A.J. Gerard Jansen ◽  
Hui Zhi Low ◽  
Judith van den Brand ◽  
Debbie van Riel ◽  
Albert Osterhaus ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Platelet Count ◽  
Viral Load ◽  
Sialic Acid ◽  
Functional Capacity ◽  
Influenza Infection ◽  
Influenza Viruses ◽  
Platelet Suspension ◽  
Platelet Counts ◽  
H5n1 Influenza

Abstract Thrombocytopenia is a common and sometimes life-threatening symptom in patients with influenza, which indicates that platelets may play a significant role during virus infection. However, the mechanisms underlying influenza associated thrombocytopenia are still unclear to date. In this study, the relationship between platelets and influenza infection was studied in vivo and in vitro. In the period 2009-2012 we randomly measured viral load and platelet count in laboratory-confirmed influenza patients (A/H1N1 subtype; n=85) presented at the emergency department of Erasmus MC. In a cross-sectional study we found, after excluding patients with HIV infection, chemotherapy treatment and immediate referral to the ICU, that a high viral load was significantly correlated with a low platelet count at presentation (n=36; Spearman correlation coefficient 0.341; P=0.042). To study this relationship further we inoculated ferrets (n=120) with an H3N2 (n=30), pandemic H1N1 (n=30), or H5N1 influenza A virus (n=30) and measured platelet counts in six ferrets per time point at day 0, 1, 2, 3 and 4 after infection. Thrombocytopenia was seen at day 3 in all ferrets compared to the control animals (n=30). The decrease in platelet counts was significant in the H5N1 infected ferrets (p<0.05). For the sialidase and influenza virus inhibitor oseltamivir, we have previously shown that it functions as an inhibitor of platelet degradation. Interestingly, thrombocytopenia in ferrets could also be inhibited by oral administration of oseltamivir. However, these results were not statistically significant. Finally, we studied the interaction between platelets and influenza viruses by electron microscopy. In a platelet suspension incubated for 1 minute with influenza virus we observed platelets with virus containing vacuoles, suggesting that the platelets had rapidly phagocytosed the viruses. Characteristics of these platelets incubated with influenza virus were measured including membrane expression of the GPIb-IX-V complex, CD62P, and surface glycans sialic acid and GlcNac using flowcytometry and functional capacity employing aggregometry using collagen, thrombin and ADP as agonists. However, no effect was seen in expression of GPIba and GPIX, P-selectin expression and surface expression of sialic acid and GlcNAc after incubation with influenza virus. Also no effect was seen on functional capacity of these platelets. Our study shows that influenza virus is significantly correlated with a lower platelet count. Phagocytosis of influenza virus by platelets may play an important role in the occurrence of thrombocytopenia during influenza infection and may be a mechanism of virus clearance during infection. Disclosures Osterhaus: Viroclinics Biosciences: Other: chief scientific officer and hold certificates of shares.

#10: Tropism, Susceptibility, and Infectivity of Differentiated Human Tonsillar Epithelial Cells by Different Influenza Viruses

2021 ◽  
Vol 10 (Supplement_2) ◽  
pp. S7-S7
Author(s):  
Faten A Okda* ◽  
Richard Webby
Keyword(s):  
Influenza Virus ◽  
Sialic Acid ◽  
Epithelial Cells ◽  
Influenza A ◽  
Influenza Infection ◽  
Influenza Viruses ◽  
H3n2 Virus ◽  
Ciliated Cells ◽  
Human Tonsil ◽  
Sialic Acid Receptors

Abstract Introduction Influenza viruses cause significant socioeconomic impact due to annual outbreaks and pandemic risks. Human tonsil epithelium cells (HTEC) are a heterogeneous group of actively differentiating epithelia comprising stratified squamous epithelium and reticulated crypt cells with abundant keratin expression. Hypothesis We hypothesized that the tonsils are a primary site for influenza infection and sustained viral replication. Methods and Results Primary HTEC (ScienCell Research Laboratories) were grown using an air-liquid interface and infected apically with different influenza viruses at various MOIs to measure viral growth kinetics. These cells were highly differentiated, with subpopulations of cells including ciliated, non-ciliated cells and specialized cells with secretory functions. There was a heterogenous distribution of both human-like (α2,6-linked) and avian-like (α2,3-linked) sialic acid receptors. The HTEC surface and crypts were lined with pseudostratified columnar ciliated cells possessing both α2,6-linked and α2,3-linked sialic acid receptors that were interrupted by patches of reticular epithelial cells. The HTEC epithelial cells were permissive for growth of influenza A and B viruses. A subset of cells, mostly ciliated cells, underwent apoptosis while others including non-ciliated cells remained intact despite being positive for influenza virus nucleoprotein. Interestingly, differences were seen between subtypes with colocalization of H3N2 virus and non-ciliated cells while H1N1 virus mostly associated with ciliated cells. Conclusion Our results implicated human tonsillar crypt epithelium as a site for influenza virus replication. The tonsil epithelium cell culture differentiated system provides a valuable in vitro model for studying cellular tropism, infectivity, cytokines immune response and the pathogenesis of influenza viruses for better development of effective universal vaccine and therapies against different strains of influenza viruses.

scholarly journals H5N1 Influenza Virus Pathogenesis in Genetically Diverse Mice Is Mediated at the Level of Viral Load

mBio ◽  
2011 ◽  
Vol 2 (5) ◽  
Author(s):  
Adrianus C. M. Boon ◽  
David Finkelstein ◽  
Ming Zheng ◽  
Guochun Liao ◽  
John Allard ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Viral Load ◽  
H5n1 Virus ◽  
Inbred Mouse ◽  
Severe Disease ◽  
Mouse Strains ◽  
H5n1 Influenza Virus ◽  
Resistant Mouse ◽  
H5n1 Influenza ◽  
Host Genetic

ABSTRACTThe genotype of the host is one of several factors involved in the pathogenesis of an infectious disease and may be a key parameter in the epidemiology of highly pathogenic H5N1 influenza virus infection in humans. Gene polymorphisms may affect the viral replication rate or alter the host’s immune response to the virus. In humans, it is unclear which aspect dictates the severity of H5N1 virus disease. To identify the mechanism underlying differential responses to H5N1 virus infection in a genetically diverse population, we assessed the host responses and lung viral loads in 21 inbred mouse strains upon intranasal inoculation with A/Hong Kong/213/03 (H5N1). Resistant mouse strains survived large inocula while susceptible strains succumbed to infection with 1,000- to 10,000-fold-lower doses. Quantitative analysis of the viral load after inoculation with an intermediate dose found significant associations with lethality as early as 2 days postinoculation, earlier than any other disease indicator. The increased viral titers in the highly susceptible strains mediated a hyperinflamed environment, indicated by the distinct expression profiles and increased production of inflammatory mediators on day 3. Supporting the hypothesis that viral load rather than an inappropriate response to the virus was the key severity-determining factor, we performed quantitative real-time PCR measuring the cytokine/viral RNA ratio. No significant differences between susceptible and resistant mouse strains were detected, confirming that it is the host genetic component controlling viral load, and therefore replication dynamics, that is primarily responsible for a host’s susceptibility to a given H5N1 virus.IMPORTANCEHighly pathogenic H5N1 influenza virus has circulated in Southeast Asia since 2003 but has been confirmed in relatively few individuals. It has been postulated that host genetic polymorphisms increase the susceptibility to infection and severe disease. The mechanisms and host proteins affected during severe disease are unknown. Inbred mouse strains vary considerably in their ability to resist H5N1 virus and were used to identify the primary mechanism determining disease severity. After inoculation with H5N1, resistant mouse strains had reduced amounts of virus in their lungs, which subsequently resulted in lower production of proinflammatory mediators and less pathology. We therefore conclude that the host genetic component controlling disease severity is primarily influencing viral replication. This is an important concept, as it emphasizes the need to limit virus replication through antiviral therapies and it shows that the hyperinflammatory environment is simply a reflection of more viral genetic material inducing a response.

scholarly journals Cross-Reactive, Cell-Mediated Immunity and Protection of Chickens from Lethal H5N1 Influenza Virus Infection in Hong Kong Poultry Markets

2001 ◽  
Vol 75 (6) ◽  
pp. 2516-2525 ◽  
Author(s):  
Sang Heui Seo ◽  
Robert G. Webster
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
Hong Kong ◽  
Virus Infection ◽  
Cellular Immunity ◽  
Influenza Virus Infection ◽  
Influenza Viruses ◽  
H5n1 Influenza Virus ◽  
H9n2 Influenza Virus ◽  
H5n1 Influenza

ABSTRACT In 1997, avian H5N1 influenza virus transmitted from chickens to humans resulted in 18 confirmed infections. Despite harboring lethal H5N1 influenza viruses, most chickens in the Hong Kong poultry markets showed no disease signs. At this time, H9N2 influenza viruses were cocirculating in the markets. We investigated the role of H9N2 influenza viruses in protecting chickens from lethal H5N1 influenza virus infections. Sera from chickens infected with an H9N2 influenza virus did not cross-react with an H5N1 influenza virus in neutralization or hemagglutination inhibition assays. Most chickens primed with an H9N2 influenza virus 3 to 70 days earlier survived the lethal challenge of an H5N1 influenza virus, but infected birds shed H5N1 influenza virus in their feces. Adoptive transfer of T lymphocytes or CD8+ T cells from inbred chickens (B2/B2) infected with an H9N2 influenza virus to naive inbred chickens (B2/B2) protected them from lethal H5N1 influenza virus. In vitro cytotoxicity assays showed that T lymphocytes or CD8+ T cells from chickens infected with an H9N2 influenza virus recognized target cells infected with either an H5N1 or H9N2 influenza virus in a dose-dependent manner. Our findings indicate that cross-reactive cellular immunity induced by H9N2 influenza viruses protected chickens from lethal infection with H5N1 influenza viruses in the Hong Kong markets in 1997 but permitted virus shedding in the feces. Our findings are the first to suggest that cross-reactive cellular immunity can change the outcome of avian influenza virus infection in birds in live markets and create a situation for the perpetuation of H5N1 influenza viruses.

scholarly journals PB1-mediated virulence attenuation of H5N1 influenza virus in mice is associated with PB2

2011 ◽  
Vol 92 (6) ◽  
pp. 1435-1444 ◽  
Author(s):  
Jing Li ◽  
Yongqiang Li ◽  
Yi Hu ◽  
Guohui Chang ◽  
Wei Sun ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Recombinant Virus ◽  
Influenza Viruses ◽  
H5n1 Influenza Virus ◽  
Wild Type ◽  
Small Plaque ◽  
Large Plaque ◽  
H5n1 Influenza ◽  
Virulence Attenuation ◽  
N Terminus

H5N1 avian influenza viruses demonstrate different phenotypes, such as pathogenicity after one or serial passages in mammalian hosts or cells. To establish the molecular basis of these phenotypes, we cloned isolates from the lungs of mice infected with human A/Vietnam/1194/2004 (H5N1) influenza virus. Large-plaque isolates were less pathogenic to mice than small-plaque isolates. Genome sequencing revealed that the small-plaque and large-plaque isolates differed in several amino acids. In order to assess their effects on pathogenicity in mice, two amino acid changes common to attenuated isolates, one in PB2 (I63T) and the other in PB1 (T677M), were inserted into a wild-type recombinant virus construct. The PB2 (I63T) or PB1 (T677M) mutations alone did not alter the phenotype of H5N1 virus, whereas recombinant virus with both mutations was less pathogenic than the wild-type recombinant virus. Furthermore, the PB1 (T677M) mutation showed a lower replication efficiency, although it had higher polymerase activity. The recombinant virus with the PB2 (63T) mutation replicated as well as the wild-type recombinant virus. These results suggest that the C terminus of PB1 of H5N1 influenza virus mediates virulence attenuation of H5N1 influenza virus in mice, associating with the N terminus of PB2. However, the role of the N terminus of PB2 in virulence attenuation in mice remains unclear.

scholarly journals A Single-Amino-Acid Substitution in a Polymerase Protein of an H5N1 Influenza Virus Is Associated with Systemic Infection and Impaired T-Cell Activation in Mice

2009 ◽  
Vol 83 (21) ◽  
pp. 11102-11115 ◽  
Author(s):  
Jamie L. Fornek ◽  
Laura Gillim-Ross ◽  
Celia Santos ◽  
Victoria Carter ◽  
Jerrold M. Ward ◽  
...  
Keyword(s):  
Immune Response ◽  
Influenza Virus ◽  
Amino Acid ◽  
T Cell ◽  
Amino Acid Substitution ◽  
Systemic Infection ◽  
Influenza Viruses ◽  
Single Amino Acid Substitution ◽  
Single Amino Acid ◽  
H5n1 Influenza

ABSTRACT The transmission of H5N1 influenza viruses from birds to humans poses a significant public health threat. A substitution of glutamic acid for lysine at position 627 of the PB2 protein of H5N1 viruses has been identified as a virulence determinant. We utilized the BALB/c mouse model of H5N1 infection to examine how this substitution affects virus-host interactions and leads to systemic infection. Mice infected with H5N1 viruses containing lysine at amino acid 627 in the PB2 protein exhibited an increased severity of lesions in the lung parenchyma and the spleen, increased apoptosis in the lungs, and a decrease in oxygen saturation. Gene expression profiling revealed that T-cell receptor activation was impaired at 2 days postinfection (dpi) in the lungs of mice infected with these viruses. The inflammatory response was highly activated in the lungs of mice infected with these viruses and was sustained at 4 dpi. In the spleen, immune-related processes including NK cell cytotoxicity and antigen presentation were highly activated by 2 dpi. These differences are not attributable solely to differences in viral replication in the lungs but to an inefficient immune response early in infection as well. The timing and magnitude of the immune response to highly pathogenic influenza viruses is critical in determining the outcome of infection. The disruption of these factors by a single-amino-acid substitution in a polymerase protein of an influenza virus is associated with severe disease and correlates with the spread of the virus to extrapulmonary sites.

scholarly journals International Laboratory Comparison of Influenza Microneutralization Assays for A(H1N1)pdm09, A(H3N2), and A(H5N1) Influenza Viruses by CONSISE

2015 ◽  
Vol 22 (8) ◽  
pp. 957-964 ◽  
Author(s):  
Karen L. Laurie ◽  
Othmar G. Engelhardt ◽  
John Wood ◽  
Alan Heath ◽  
Jacqueline M. Katz ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Incubation Time ◽  
Influenza A ◽  
Influenza Viruses ◽  
Enzyme Linked Immunosorbent Assay ◽  
Influenza A Viruses ◽  
H5n1 Influenza ◽  
The World ◽  
International Laboratory ◽  
The Impact

ABSTRACTThe microneutralization assay is commonly used to detect antibodies to influenza virus, and multiple protocols are used worldwide. These protocols differ in the incubation time of the assay as well as in the order of specific steps, and even within protocols there are often further adjustments in individual laboratories. The impact these protocol variations have on influenza serology data is unclear. Thus, a laboratory comparison of the 2-day enzyme-linked immunosorbent assay (ELISA) and 3-day hemagglutination (HA) microneutralization (MN) protocols, using A(H1N1)pdm09, A(H3N2), and A(H5N1) viruses, was performed by the CONSISE Laboratory Working Group. Individual laboratories performed both assay protocols, on multiple occasions, using different serum panels. Thirteen laboratories from around the world participated. Within each laboratory, serum sample titers for the different assay protocols were compared between assays to determine the sensitivity of each assay and were compared between replicates to assess the reproducibility of each protocol for each laboratory. There was good correlation of the results obtained using the two assay protocols in most laboratories, indicating that these assays may be interchangeable for detecting antibodies to the influenza A viruses included in this study. Importantly, participating laboratories have aligned their methodologies to the CONSISE consensus 2-day ELISA and 3-day HA MN assay protocols to enable better correlation of these assays in the future.

scholarly journals Swine Influenza Virus PA and Neuraminidase Gene Reassortment into Human H1N1 Influenza Virus Is Associated with an Altered Pathogenic Phenotype Linked to Increased MIP-2 Expression

2015 ◽  
Vol 89 (10) ◽  
pp. 5651-5667 ◽  
Author(s):  
Daniel Dlugolenski ◽  
Les Jones ◽  
Elizabeth Howerth ◽  
David Wentworth ◽  
S. Mark Tompkins ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Sialic Acid ◽  
Influenza A ◽  
H1n1 Virus ◽  
Swine Influenza ◽  
Influenza Viruses ◽  
Pandemic H1n1 ◽  
Human Influenza ◽  
Swine Virus ◽  
Virus Reassortment

ABSTRACTSwine are susceptible to infection by both avian and human influenza viruses, and this feature is thought to contribute to novel reassortant influenza viruses. In this study, the influenza virus reassortment rate in swine and human cells was determined. Coinfection of swine cells with 2009 pandemic H1N1 virus (huH1N1) and an endemic swine H1N2 (A/swine/Illinois/02860/09) virus (swH1N2) resulted in a 23% reassortment rate that was independent of α2,3- or α2,6-sialic acid distribution on the cells. The reassortants had altered pathogenic phenotypes linked to introduction of the swine virus PA and neuraminidase (NA) into huH1N1. In mice, the huH1N1 PA and NA mediated increased MIP-2 expression early postinfection, resulting in substantial pulmonary neutrophilia with enhanced lung pathology and disease. The findings support the notion that swine are a mixing vessel for influenza virus reassortants independent of sialic acid distribution. These results show the potential for continued reassortment of the 2009 pandemic H1N1 virus with endemic swine viruses and for reassortants to have increased pathogenicity linked to the swine virus NA and PA genes which are associated with increased pulmonary neutrophil trafficking that is related to MIP-2 expression.IMPORTANCEInfluenza A viruses can change rapidly via reassortment to create a novel virus, and reassortment can result in possible pandemics. Reassortments among subtypes from avian and human viruses led to the 1957 (H2N2 subtype) and 1968 (H3N2 subtype) human influenza pandemics. Recent analyses of circulating isolates have shown that multiple genes can be recombined from human, avian, and swine influenza viruses, leading to triple reassortants. Understanding the factors that can affect influenza A virus reassortment is needed for the establishment of disease intervention strategies that may reduce or preclude pandemics. The findings from this study show that swine cells provide a mixing vessel for influenza virus reassortment independent of differential sialic acid distribution. The findings also establish that circulating neuraminidase (NA) and PA genes could alter the pathogenic phenotype of the pandemic H1N1 virus, resulting in enhanced disease. The identification of such factors provides a framework for pandemic modeling and surveillance.

scholarly journals Mapping of a Novel H3-Specific Broadly Neutralizing Monoclonal Antibody Targeting the Hemagglutinin Globular Head Isolated from an Elite Influenza Virus-Immunized Donor Exhibiting Serological Breadth

2019 ◽  
Vol 94 (6) ◽  
Author(s):  
Yu Qiu ◽  
Svetlana Stegalkina ◽  
Jianxin Zhang ◽  
Ekaterina Boudanova ◽  
Anna Park ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Sialic Acid ◽  
Neutralizing Antibodies ◽  
Vaccine Design ◽  
Binding Pocket ◽  
Influenza Viruses ◽  
Antigenic Drift ◽  
Human Antibody ◽  
Sialic Acid Binding ◽  
Globular Head

ABSTRACT The discovery of potent and broadly protective influenza virus epitopes could lead to improved vaccines that are resistant to antigenic drift. Here, we describe human antibody C585, isolated from a vaccinee with remarkable serological breadth as measured by hemagglutinin inhibition (HAI). C585 binds and neutralizes multiple H3N2 strains isolated between 1968 and 2016, including strains that emerged up to 4 years after B cells were isolated from the vaccinated donor. The crystal structure of C585 Fab in complex with the HA from A/Switzerland/9715293/2013 (H3N2) shows that the antibody binds to a novel and well-conserved epitope on the globular head of H3 HA and that it differs from other antibodies not only in its epitope but in its binding geometry and hypermutated framework 3 region, thereby explaining its breadth and ability to mediate hemagglutination inhibition across decades of H3N2 strains. The existence of epitopes such as the one elucidated by C585 has implications for rational vaccine design. IMPORTANCE Influenza viruses escape immunity through continuous antigenic changes that occur predominantly on the viral hemagglutinin (HA). Induction of broadly neutralizing antibodies (bnAbs) targeting conserved epitopes following vaccination is a goal of universal influenza vaccines and advantageous in protecting hosts against virus evolution and antigenic drift. To date, most of the discovered bnAbs bind either to conserved sites in the stem region or to the sialic acid-binding pocket. Generally, antibodies targeting the stem region offer broader breadth with low potency, while antibodies targeting the sialic acid-binding pocket cover narrower breadth but usually have higher potency. In this study, we identified a novel neutralizing epitope in the head region recognized by a broadly neutralizing human antibody against a broad range of H3N2 with high potency. This epitope may provide insights for future universal vaccine design.

scholarly journals RNA-Sequencing-Based Transcriptomic Analysis Reveals a Role for Annexin-A1 in Classical and Influenza A Virus-Induced Autophagy

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1399 ◽  
Author(s):  
Jianzhou Cui ◽  
Dhakshayini Morgan ◽  
Dao Han Cheng ◽  
Sok Lin Foo ◽  
Gracemary L. R. Yap ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A Virus ◽  
Influenza A ◽  
Influenza Infection ◽  
Critical Role ◽  
Mtor Inhibitors ◽  
Influenza Viruses ◽  
Annexin A1 ◽  
Underlying Mechanisms

Influenza viruses have been shown to use autophagy for their survival. However, the proteins and mechanisms involved in the autophagic process triggered by the influenza virus are unclear. Annexin-A1 (ANXA1) is an immunomodulatory protein involved in the regulation of the immune response and Influenza A virus (IAV) replication. In this study, using clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 (CRISPR associated protein 9) deletion of ANXA1, combined with the next-generation sequencing, we systematically analyzed the critical role of ANXA1 in IAV infection as well as the detailed processes governing IAV infection, such as macroautophagy. A number of differentially expressed genes were uniquely expressed in influenza A virus-infected A549 parental cells and A549 ∆ANXA1 cells, which were enriched in the immune system and infection-related pathways. Gene ontology and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway revealed the role of ANXA1 in autophagy. To validate this, the effect of mechanistic target of rapamycin (mTOR) inhibitors, starvation and influenza infection on autophagy was determined, and our results demonstrate that ANXA1 enhances autophagy induced by conventional autophagy inducers and influenza virus. These results will help us to understand the underlying mechanisms of IAV infection and provide a potential therapeutic target for restricting influenza viral replication and infection.

scholarly journals Are Ducks Contributing to the Endemicity of Highly Pathogenic H5N1 Influenza Virus in Asia?

2005 ◽  
Vol 79 (17) ◽  
pp. 11269-11279 ◽  
Author(s):  
K. M. Sturm-Ramirez ◽  
D. J. Hulse-Post ◽  
E. A. Govorkova ◽  
J. Humberd ◽  
P. Seiler ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Virus Disease ◽  
Influenza Viruses ◽  
H5n1 Influenza Virus ◽  
Highly Pathogenic ◽  
Main Site ◽  
H5n1 Influenza ◽  
Pathogenic H5n1 ◽  
Virus Isolates

ABSTRACT Wild waterfowl are the natural reservoir of all influenza A viruses, and these viruses are usually nonpathogenic in these birds. However, since late 2002, H5N1 outbreaks in Asia have resulted in mortality among waterfowl in recreational parks, domestic flocks, and wild migratory birds. The evolutionary stasis between influenza virus and its natural host may have been disrupted, prompting us to ask whether waterfowl are resistant to H5N1 influenza virus disease and whether they can still act as a reservoir for these viruses. To better understand the biology of H5N1 viruses in ducks and attempt to answer this question, we inoculated juvenile mallards with 23 different H5N1 influenza viruses isolated in Asia between 2003 and 2004. All virus isolates replicated efficiently in inoculated ducks, and 22 were transmitted to susceptible contacts. Viruses replicated to higher levels in the trachea than in the cloaca of both inoculated and contact birds, suggesting that the digestive tract is not the main site of H5N1 influenza virus replication in ducks and that the fecal-oral route may no longer be the main transmission path. The virus isolates' pathogenicities varied from completely nonpathogenic to highly lethal and were positively correlated with tracheal virus titers. Nevertheless, the eight virus isolates that were nonpathogenic in ducks replicated and transmitted efficiently to naïve contacts, suggesting that highly pathogenic H5N1 viruses causing minimal signs of disease in ducks can propagate silently and efficiently among domestic and wild ducks in Asia and that they represent a serious threat to human and veterinary public health.

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