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ARS Home » Midwest Area » Ames, Iowa » National Animal Disease Center » Virus and Prion Research » Research » Publications at this Location » Publication #409635

Research Project: Intervention Strategies to Control Endemic and New and Emerging Influenza A Virus Infections in Swine

Location: Virus and Prion Research

Title: Amino acid 138 in the HA of a H3N2 subtype influenza A virus increases affinity for the lower respiratory tract and alveolar macrophages in pigs

item CARDENAS, MATIAS - University Of Georgia
item SEIBERT, BRITTANY - University Of Georgia
item COWAN, BRIANNA - University Of Georgia
item FRAIHA, ANA LUIZA - University Of Georgia
item CARNACCINI, SILVIA - University Of Georgia
item GAY, CLAIRE - University Of Georgia
item FACCIN, FLAVIO CARGNIN - University Of Georgia
item CACERES, JOAQUIN - University Of Georgia
item Anderson, Tavis
item Baker, Amy
item PEREZ, DANIEL - University Of Georgia
item RAJAO, DANIELA - University Of Georgia

Submitted to: PLoS Pathogens
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/5/2024
Publication Date: 2/20/2024
Citation: Cardenas, M., Seibert, B., Cowan, B., Fraiha, A.S., Carnaccini, S., Gay, C.L., Faccin, F., Caceres, J.C., Anderson, T.K., Baker, A.L., Perez, D.R., Rajao, D.S. 2024. Amino acid 138 in the HA of a H3N2 subtype influenza A virus increases affinity for the lower respiratory tract and alveolar macrophages in pigs. PLoS Pathogens.

Interpretive Summary: Human-to-swine influenza A virus (IAV) spillover events are relatively common and have led to the establishment of multiple evolutionarily distinct virus lineages in the swine population worldwide, leading to important economic losses in the pork industry. This also increases the risk of reassortment and emergence of novel IAV that may retain the ability to infect and transmit in humans, an event exemplified by the H1N1 pandemic in 2009. However, the molecular mechanisms driving IAV adaptation to pigs following the introduction of a human virus into the host are still not fully understood. In this study we found that a point mutation in a human-origin hemagglutinin (HA) affects both HA avidity and neuraminidase (NA) activity, ultimately improving infection and transmissibility in pigs characterized by an enhanced lung replication and the disruption of lung-resident immune cell populations. This relationship between improved replication and infectivity of lung-resident cells provides insights into host barriers limiting human IAV adaptation to pigs and the complexities associated with the host immune response that influenza A viruses must overcome to become established in the swine population.

Technical Abstract: Influenza A virus (FLUAV) infects a wide range of hosts and human-to-swine spillover events are frequently reported. However, only a few of these human viruses have become established in pigs and the host barriers and molecular mechanisms driving adaptation to the swine host remain poorly understood. We previously found that infection of pigs with a 2:6 reassortant virus (hVIC/11) containing the hemagglutinin (HA) and neuraminidase (NA) gene segments from the human strain A/Victoria/361/2011 (H3N2) and internal gene segments of an endemic swine strain (sOH/04) resulted in a fixed amino acid substitution in the HA (A138S, matured H3 HA numbering). To understand the role of the HA A138S substitution in the adaptation of a human-origin FLUAV HA to swine, we infected pigs with the hVIC/11A138S mutant and analyzed pathogenesis and transmission compared to hVIC/11 and sOH/04. Our results showed that the hVIC/11A138S virus had an intermediary pathogenesis between hVIC/11 and sOH/04. The hVIC/11A138S infected the upper respiratory tract, right caudal, and both cranial lobes while hVIC/11 was only detected in nose and trachea samples. Viruses induced a distinct expression pattern of a various pro-inflammatory cytokines such as IL-8, TNF-', and IFN-'. Flow cytometric analysis of lung samples revealed a significant reduction of porcine alveolar macrophages (PAMs) in hVIC/11A138S-infected pigs compared to sOH/04 while a MHCIIlowCD163neg population was increased. The hVIC/11A138S showed a higher affinity for PAMs than hVIC/11 noted as an increase of infected PAMs in bronchoalveolar lavage fluid (BALF) and showed no differences in the percentage of HA-positive PAMs compared to sOH/04. This increased infection of PAMs led to an overexpression of granulocyte-monocyte colony-stimulating factor (GM-CSF) stimulation but a reduced expression of peroxisome proliferator-activated receptor gamma (PPAR') in the sOH/04-infected group. Analysis using the PAM cell line 3D4/21 revealed that the A138S substitution improved replication and apoptosis induction in this cell type compared to hVIC/11 but at lower levels than sOH/04. Overall, our study indicates that adaptation of human viruses to the swine host involves an increased affinity for the lower respiratory tract and alveolar macrophages.