key: cord-0804052-gmofny2g
authors: Banerjee, Arinjay; Mossman, Karen L.; Miller, Matthew S.
title: Bat influenza viruses: Making a double agent of MHC class II
date: 2020-04-20
journal: Trends Microbiol
DOI: 10.1016/j.tim.2020.04.006
sha: 17818d663b9a6036d4b93b59d2897c4bdf620e9d
doc_id: 804052
cord_uid: gmofny2g

Abstract Major histocompatibility complex class II has recently been identified as a cellular receptor for bat influenza viruses. Here, we discuss the possible implications of viral exploitation of this critical host defense molecule and highlight the need for more intense study of bat-influenza virus interactions.

J o u r n a l P r e -p r o o f 2 several questions about the evolution, host range, tropism, and transmission potential of these viruses.

The hemagglutinin (HA) of avian IAVs have a preference for sialic acids that display an 2, 3- linkage to the penultimate sugar, whereas human IAVs preferentially bind to the 2,6 linkage [4, 5] . In two striking studies, Karakus et al. and Giotis et al. identified major histocompatibility complex class II (MHCII) as a receptor for bat H17N10 and H18N11 viruses [6, 7] . Karakus et al. used transcriptomic profiling and genome-wide CRISPR-Cas9 screening of susceptible and non-susceptible cells to identify and characterize MHCII as an entry determinant for bat H17N10 and H18N11 viruses [6] . The authors also observed that bat H17N10 and H18N11 viruses could initiate virus entry via MHCII homologs encoded by multiple bat species, pigs, humans and chickens [6] . In a subsequent study, Giotis et The use of MHCII as a receptor is unique to bat H17N10 and H18N11 influenza viruses, which might suggest altered cellular tropism relative to other known IAVs. In bats, H17N10 RNA was detected in liver, kidney, lung and intestinal tissues, whereas H18N11 RNA was found exclusively in the intestine [1] . Ciminski et al. indeed demonstrated that in bats experimentally infected with H18N11, virus could be detected in the feces and transmitted to co-housed naïve bats, presumably via the fecal-oral route [8] . This is akin to the behavior of avian influenza viruses in waterfowl. Going forward, it will be important to determine with greater resolution the specific cell types that are permissive for replication of H17N10 and H18N11 viruses in bats. in response to infection [8] . Nevertheless, it will be interesting to determine whether H18N11 infection impairs T cell activation and as a result, the breadth and quality of the antibody response ( Figure 1 ).

Emerging data have suggested that broadly-neutralizing antibodies are capable of neutralizing H17N10 viruses [10] . However, the titers and prevalence of antibodies capable of neutralizing bat H17 and H18 viruses in humans have not yet been studied. It will be interesting to determine whether humans and other species in areas where bat influenza viruses are endemic (i.e. South America) have already been exposed to these viruses and have mounted specific adaptive immune responses. Sero-epidemiological studies could shed important light on this question.

The observed inability of bat influenza viruses to efficiently transmit within mice and ferrets, alongside their limited reassortment potential with conventional IAVs (reviewed in [11] ) reduces the probability that these viruses pose an imminent zoonotic threat. However, that does not rule out the potential for epizootic transmission. Yet, gene segments of bat H17N10 and H18N11 viruses are compatible for reassortment [12] . Important questions therefore remain regarding the true diversity of bat influenza viruses, and their evolutionary relationship to conventional IAVs.

Frugivorous and insectivorous bats diverged over 50 million years ago and there are over 1400 known species of bats. Although H17N10 and H18N11 viruses have only been detected in New World fruit bats (Table 1) , in vitro studies with pseudotyped viruses demonstrated that ectopically-expressed MHCII from insectivorous bats, Eptesicus fuscus and Myotis lucifugus was J o u r n a l P r e -p r o o f 6 sufficient to serve as a cellular receptor for entry of these viruses [6] . Thus, there is a pressing need to perform more detailed and systematic surveys of multiple bat species in different geographical locations to better understand the prevalence and diversity of bat influenza viruses.

The growing frequency of outbreaks caused by emerging viruses reinforces the critical need to adopt a "One Health" approach to effectively control infectious diseases. Bats have proven to be an especially important reservoir for many pathogens with zoonotic potential, including SARS-CoV, SARS-CoV-2 and Ebola virus. The discovery and ongoing characterization of bat influenza viruses highlights the unpredictable nature of IAVs and the need for more intense study of their evolutionary diversity and pathobiology, especially in non-human hosts. 

A distinct lineage of influenza A virus from bats

New world bats harbor diverse influenza A viruses

Bat Influenza A(HL18NL11) Virus in Fruit Bats

The structure and receptor binding properties of the 1918 influenza hemagglutinin

Structure of the influenza virus haemagglutinin complexed with its receptor, sialic acid

MHC class II proteins mediate cross-species entry of bat influenza viruses

Entry of the bat influenza H17N10 virus into mammalian cells is enabled by the MHC class II HLA-DR receptor

Bat influenza viruses transmit among bats but are poorly adapted to non-bat species

The ins and outs of MHC class II-mediated antigen processing and presentation

The bat influenza H17N10 can be neutralized by broadly-neutralizing monoclonal antibodies and its neuraminidase can facilitate viral egress

Novel insights into bat influenza A viruses

Characterization of uncultivable bat influenza virus using a replicative synthetic virus