Sialic acid recognition is a key determinant of influenza A virus tropism in murine trachea epithelial cell cultures

Pekosz, Andrew; Newby, Celeste M.; Bose, Pulkit S.; Lutz, Andrew

doi:10.1016/j.virol.2009.01.005

Cited by 36 publications

(36 citation statements)

References 53 publications

(100 reference statements)

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“…In human H3 viruses, amino acid positions D190, L/I226, and S228 correlated with SA␣-2,6 receptors, while in swine H3 viruses those positions are D/A190, V226, and S228 (27,40,46). All three isolates-A/IN A(H3N2)v, Sw/PA H3N2-TRIG, and Sw/IL rH3N2p-were able to infect and transmit to contact pigs.…”

Section: Discussionmentioning

confidence: 94%

Pathogenicity and Transmission in Pigs of the Novel A(H3N2)v Influenza Virus Isolated from Humans and Characterization of Swine H3N2 Viruses Isolated in 2010-2011

Kitikoon

Vincent

Gauger

et al. 2012

J Virol

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Swine influenza virus (SIV) H3N2 with triple reassorted internal genes (TRIG) has been enzootic in Unites States since 1998. Transmission of the 2009 pandemic H1N1 (pH1N1) virus to pigs in the United States was followed by reassortment with endemic SIV, resulting in reassorted viruses that include novel H3N2 genotypes (rH3N2p). Between July and December 2011, 12 cases of human infections with swine-lineage H3N2 viruses containing the pandemic matrix (pM) gene [A(H3N2)v] were detected. Whole-genome analysis of H3N2 viruses isolated from pigs from 2009 to 2011 sequenced in this study and other available H3N2 sequences showed six different rH3N2p genotypes present in the U.S. swine population since 2009. The presence of the pM gene was a common feature among all rH3N2p genotypes, but no specific genotype appeared to predominate in the swine population. We compared the pathogenic, transmission, genetic, and antigenic properties of a human A(H3N2)v isolate and two swine H3N2 isolates, H3N2-TRIG and rH3N2p. Our in vivo study detected no increased virulence in A(H3N2)v or rH3N2p viruses compared to endemic H3N2-TRIG virus. Antibodies to cluster IV H3N2-TRIG and rH3N2p viruses had reduced cross-reactivity to A(H3N2)v compared to other cluster IV H3N2-TRIG and rH3N2p viruses. Genetic analysis of the hemagglutinin gene indicated that although rH3N2p and A(H3N2)v are related to cluster IV of H3N2-TRIG, some recent rH3N2p isolates appeared to be forming a separate cluster along with the human isolates of A(H3N2)v. Continued monitoring of these H3N2 viruses is necessary to evaluate the evolution and potential loss of population immunity in swine and humans.

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Section: Discussionmentioning

confidence: 94%

Pathogenicity and Transmission in Pigs of the Novel A(H3N2)v Influenza Virus Isolated from Humans and Characterization of Swine H3N2 Viruses Isolated in 2010-2011

Kitikoon

Vincent

Gauger

et al. 2012

J Virol

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“…It should be noted that the absence of pulmonary PR8 infection after URT delivery of virus was not due to a higher susceptibility of the virus to innate inhibitors in the LRT, since PR8 virus grew to high titers in the lungs after TRT infection. In addition, the inability of PR8 virus to progress to the lungs is independent of receptor specificity, as both viral strains have the capacity to infect cells bearing sialic acid in ␣2-3 linkage (20)(21)(22) to galactose, which is found on the receptors for influenza virus throughout the mouse respiratory tract and is used when these viruses grow in the lungs after TRT delivery (Fig. 1).…”

Section: Resultsmentioning

confidence: 99%

Salivary Blockade Protects the Lower Respiratory Tract of Mice from Lethal Influenza Virus Infection

Ivinson

Deliyannis

McNabb

et al. 2017

J Virol

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It is possible to model the progression of influenza virus from the upper respiratory tract to the lower respiratory tract in the mouse using viral inoculum delivered in a restricted manner to the nose. In this model, infection with the A/Udorn/ 307/72 (Udorn) strain of virus results ultimately in high viral titers in both the trachea and lungs. In contrast, the A/Puerto Rico/8/34 (PR8) strain causes an infection that is almost entirely limited to the nasal passages. The factors that govern the progression of virus down the respiratory tract are not well understood. Here, we show that, while PR8 virus grows to high titers in the nose, an inhibitor present in the saliva blocks further progression of infection to the trachea and lungs and renders an otherwise lethal dose of virus completely asymptomatic. In vitro, the salivary inhibitor was capable of potent neutralization of PR8 virus and an additional 20 strains of type A virus and two type B strains that were tested. The exceptions were Udorn virus and the closely related H3N2 strains A/Port Chalmers/1/73 and A/Victoria/3/75. Characterization of the salivary inhibitor showed it to be independent of sialic acid and other carbohydrates for its function. This and other biochemical properties, together with its virus strain specificity and in vivo function, indicate that the mouse salivary inhibitor is a previously undescribed innate inhibitory molecule that may have evolved to provide pulmonary protection of the species from fatal influenza virus infection. IMPORTANCE Influenza A virus occasionally jumps from aquatic birds, its natural host, into mammals to cause outbreaks of varying severity, including pandemics in humans. Despite the laboratory mouse being used as a model to study influenza virus pathogenesis, natural outbreaks of influenza have not been reported in the species. Here, we shed light on one mechanism that might allow mice to be protected from influenza in the wild. We show that virus deposited in the mouse upper respiratory tract will not progress to the lower respiratory tract due to the presence of a potent inhibitor of the virus in saliva. Containing inhibitor-sensitive virus to the upper respiratory tract renders an otherwise lethal infection subclinical. This knowledge sheds light on how natural inhibitors may have evolved to improve survival in this species.KEYWORDS influenza, innate inhibitors I nfluenza A virus (IAV) is a respiratory pathogen of global significance, responsible for 250,000 to 500,000 deaths annually. Innate immunity is critical to the host in the early stages of IAV infection, restricting the escalation of viral loads prior to the induction of virus-clearing responses mediated by the adaptive immune system. As part of the innate immune system, a variety of soluble molecules are present in respiratory secretions to provide an initial barrier to infection. They include collectins, pentraxins,

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“…Previous studies have shown that IAV preferentially replicate in tracheal epithelial cells (8,26). We analyzed the sites of initial viral replication and the spreading from these sites in the murine model by performing whole-organ imaging of NS1-GFP-infected lungs.…”

Section: Discussionmentioning

confidence: 99%

Analysis of in vivo dynamics of influenza virus infection in mice using a GFP reporter virus

Manicassamy

Belicha-Villanueva

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

382

483

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Influenza A virus is being extensively studied because of its major impact on human and animal health. However, the dynamics of influenza virus infection and the cell types infected in vivo are poorly understood. These characteristics are challenging to determine, partly because there is no efficient replication-competent virus expressing an easily traceable reporter gene. Here, we report the generation of a recombinant influenza virus carrying a GFP reporter gene in the NS segment (NS1-GFP virus). Although attenuated when compared with wild-type virus, the NS1-GFP virus replicates efficiently in murine lungs and shows pathogenicity in mice. Using whole-organ imaging and flow cytometry, we have tracked the dynamics of influenza virus infection progression in mice. Imaging of murine lungs shows that infection starts in the respiratory tract in areas close to large conducting airways and later spreads to deeper sections of the lungs. In addition to epithelial cells, we found GFP-positive antigen-presenting cells, such as CD11b + CD11c , as early as 24 h after intranasal infection. In addition, a significant proportion of NK and B cells were GFP positive, suggesting active infection of these cells. We next tested the effects of the influenza virus inhibitors oseltamivir and amantadine on the kinetics of in vivo infection progression. Treatment with oseltamivir dramatically reduced influenza infection in all cell types, whereas, surprisingly, amantadine treatment more efficiently blocked infection in B and NK cells. Our results demonstrate high levels of immune cells harboring influenza virus antigen during viral infection and cell-typespecific effects upon treatment with antiviral agents, opening additional avenues of research in the influenza virus field.antivirals | pathogenesis | recombinant influenza virus | GFP virus | cell tropism I nfluenza A virus (IAV), a member of the Orthomyxoviridae family, causes respiratory disease that can be very severe, especially in very young children and elderly individuals (1). Apart from yearly seasonal outbreaks, IAV can cause frequent epidemics and occasional pandemics in humans (2, 3). Vaccination has been one of the most effective means of protection against influenza virus infection. In addition, there are two categories of Food and Drug Administration-approved drugs used for treatment of IAV infections: (i) M2 inhibitors, which block viral uncoating and entry (amantadine and rimantadine); and (ii) NA inhibitors, which block viral spreading (oseltamivir and zanamivir; reviewed in refs. 4-7).Although studies on IAV using animal models and tissue culture have provided tremendous knowledge about both the viral and host factors that determine pathogenesis, following viral infection in vivo may provide us with a more complete picture of the complex interactions between the virus and the host (8). Such in vivo studies have been hampered primarily due to the lack of fully virulent IAV-expressing reporter genes that can be easily detected in vivo. Previous studies have attempted ...

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Sialic acid recognition is a key determinant of influenza A virus tropism in murine trachea epithelial cell cultures

Cited by 36 publications

References 53 publications

Pathogenicity and Transmission in Pigs of the Novel A(H3N2)v Influenza Virus Isolated from Humans and Characterization of Swine H3N2 Viruses Isolated in 2010-2011

Pathogenicity and Transmission in Pigs of the Novel A(H3N2)v Influenza Virus Isolated from Humans and Characterization of Swine H3N2 Viruses Isolated in 2010-2011

Salivary Blockade Protects the Lower Respiratory Tract of Mice from Lethal Influenza Virus Infection

Analysis of in vivo dynamics of influenza virus infection in mice using a GFP reporter virus

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