An infant mouse model of influenza virus transmission demonstrates the role of virus-specific shedding, humoral immunity, and sialidase expression by colonizingStreptococcus pneumoniae

Abstract

1 9 2 0 2 1 2 2 Word count: Abstract (368), Text (4692) 2 3 2 ABSTRACT 2 4 2 5The pandemic potential of influenza A viruses (IAV) depends on the infectivity of 2 6 the host, transmissibility of the virus, and susceptibility of the recipient. While virus traits 2 7 supporting IAV transmission have been studied in detail using ferret and guinea pig 2 8 models, there is limited understanding of host traits determining transmissibility and 2 9 susceptibility because current animal models of transmission are not sufficiently 3 0 tractable. Although mice remain the primary model to study IAV immunity and 3 1 pathogenesis, the efficiency of IAV transmission in adult mice has been inconsistent. 2Here we describe an infant mouse model which support efficient transmission of IAV. 3We demonstrate that transmission in this model requires young age, close contact, 3 4 shedding of virus particles from the upper respiratory tract (URT) of infected pups, the 3 5 use of a transmissible virus strain, and a susceptible recipient. We characterize 3 6shedding as a marker of infectiousness that predicts the efficiency of transmission 3 7 among different influenza virus strains. We also demonstrate that transmissibility and 3 8 susceptibility to IAV can be inhibited by humoral immunity via maternal-infant transfer of 3 9 IAV-specific immunoglobulins, and modifications to the URT milieu, via sialidase activity 4 0 of colonizing Streptococcus pneumoniae (Spn). Due to its simplicity and efficiency, this 4 1 model can be used to dissect the host's contribution to IAV transmission and explore 4 2 new methods to limit contagion.4 3 3 IMPORTANCE 4 4 4 5This study provides insight into the role of the virus strain, age, immunity, and 4 6 URT flora on IAV shedding and transmission efficiency. Using the infant mouse model, 4 7 we found that: (a) differences in viral shedding of various IAV strains is dependent on 4 8 specific hemagglutinin (HA) and/or neuraminidase (NA) proteins; (b) host age plays a 4 9 key role in the efficiency of IAV transmission; (c) levels of IAV-specific immunoglobulins 5 0 are necessary to limit infectiousness, transmission, and susceptibility to IAV; and (d) 5 1 expression of sialidases by colonizing Spn antagonize transmission by limiting the 5 2 acquisition of IAV in recipient hosts. Our findings highlight the need for strategies that 5 3 limit IAV shedding, and the importance of understanding the function of the URT 5 4 bacterial composition in IAV transmission. This work reinforces the significance of a 5 5tractable animal model to study both viral and host traits affecting IAV contagion, and its 5 6 potential for optimizing vaccines and therapeutics that target disease spread. 5 7 5 8 5 9

Pneumococcal colonization impairs mucosal immune responses to Live Attenuated Influenza Vaccine in adults

“…We investigated the cellular and humoral immune responses elicited by TIV and LAIV, focusing on respiratory mucosa, and assessed whether colonization of the nasopharynx with S. pneumoniae influences vaccine immunogenicity. In agreement with previous studies 3 pneumoniae-IAV coinfection model (46). In light of these observations, it would also be interesting to investigate to what extent symptoms and inflammation caused by wild type influenza viruses are altered by concurrent Spn colonization in humans.…”

Coinfection ofStreptococcus pneumoniaereduces airborne transmission of influenza virus

“…Surprisingly, we observed that coinfection with Spn decreased H1N1pdm09 replication in URT as determined by viral titration of nasal washes. This observation is similar to recent data obtained from neonatal mice colonized with Spn prior to PR8 H1N1 infection (Ortigoza et al, 2018). The difference in enhancement of Spn colonization versus reduction in viral titers indicates an asymmetrical relationship between these two pathogens.…”

“…There are numerable ways the microbiota could influence attachment and entry of IAV into host cells, IAV replication, maturation of viruses with host cells, egress and dissemination, and interaction between coinfecting viral and bacterial pathogens (Jones, Le Sage, & Lakdawala, 2020). It is already clear that changes in glycosylation of the host incurred during IAV infection influence subsequent Spn colonization, and similarly changes in glycosylation via Spn affect subsequent IAV infection (Ortigoza et al, 2018; Siegel et al, 2014). It is likely that changes in host glycosylation by Spn and other bacteria also influence entry and egress of IAV, as well as its distribution in tissues across the respiratory tract.…”

“…Contact-dependent transmission studies performed in infant mice clearly show that coinfection with IAV dramatically enhances Spn transmission with the efficiency of IAV being highly variable (Diavatopoulos et al, 2010; Short, Reading, Wang, Diavatopoulos, & Wijburg, 2012). Further, recent studies in the neonatal murine model have demonstrated that Spn infection preceding IAV inoculation can decrease IAV transmission (Ortigoza, Blaser, Zafar, Hammond, & Weiser, 2018). However, adult mice are a suboptimal model for IAV transmission since they are not susceptible to human seasonal influenza virus strains, and transmission of mouse adapted IAV is inefficient (Bouvier, 2015).…”

Quo vadis? Central Rules of Pathogen and Disease Tropism

“…The microbiota can also directly interfere with or promote invasion by the pathogen. For example, successful influenza A virus transmission is inhibited by nasal carriage of Streptococcus pneumoniae , which cleaves host nasal sialic acid, the receptor for influenza ( Ortigoza et al., 2018 ).…”