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Continuously emerging variants of concern (VOCs) sustain the SARS-CoV-2 pandemic. The SARS-CoV-2 Omicron/B.1.1.529 VOC harbours multiple mutations in the spike protein associated with high infectivity and efficient evasion from humoral immunity induced by previous infection or vaccination. By performing in-depth comparisons of the SARS-CoV-2-specific T-cell epitope repertoire after infection and messenger RNA vaccination, we demonstrate that spike-derived epitopes were not dominantly targeted in convalescent individuals compared to non-spike epitopes. In vaccinees, however, we detected a broader spike-specific T-cell response compared to convalescent individuals. Booster vaccination increased the breadth of the spike-specific T-cell response in convalescent individuals but not in vaccinees with complete initial vaccination. In convalescent individuals and vaccinees, the targeted T-cell epitopes were broadly conserved between wild-type SARS-CoV-2 variant B and Omicron/B.1.1.529. Hence, our data emphasize the relevance of vaccine-induced spike-specific CD8+ T-cell responses in combating VOCs including Omicron/B.1.1.529 and support the benefit of boosting convalescent individuals with mRNA vaccines.

An Old-World bat H9N2 influenza A virus (IAV) identified in Egypt exhibits high replication and transmission potential in ferrets, efficient infection of human lung explant cultures and marked escape from the antiviral activity of MxA. Together with low antigenic similarity to N2 of seasonal human strains, bat H9N2 meets key criteria for pre-pandemic IAVs.

SARS-CoV-2 spike mRNA vaccines1–3 mediate protection from severe disease as early as ten days after prime vaccination3, when neutralizing antibodies are hardly detectable4–6. Vaccine-induced CD8+ T cells may therefore be the main mediators of protection at this early stage7,8. The details of their induction, comparison to natural infection, and association with other arms of vaccine-induced immunity remain, however, incompletely understood. Here we show on a single-epitope level that a stable and fully functional CD8+ T cell response is vigorously mobilized one week after prime vaccination with bnt162b2, when circulating CD4+ T cells and neutralizing antibodies are still weakly detectable. Boost vaccination induced a robust expansion that generated highly differentiated effector CD8+ T cells; however, neither the functional capacity nor the memory precursor T cell pool was affected. Compared with natural infection, vaccine-induced early memory T cells exhibited similar functional capacities but a different subset distribution. Our results indicate that CD8+ T cells are important effector cells, are expanded in the early protection window after prime vaccination, precede maturation of other effector arms of vaccine-induced immunity and are stably maintained after boost vaccination.

Previous influenza A virus (IAV) pandemics have invariably been caused by the introduction of an emergent IAV strain from an animal host into a human population with no or only little pre-existing immunity to the novel strain. Although zoonotic spillover of IAVs into humans can be associated with severe disease and a high fatality rate, these strains are typically poorly adapted to humans and are unable to establish sustained transmission between humans. Given the presumably very high degree of exposure to animal populations with endemic IAV, the number of pandemics remains surprisingly low. In this review, we provide an updated perspective on the molecular mechanisms underlying the adaptation of zoonotic IAV to human hosts, and discuss the implications for future pandemics.

Reports of waning immunity after COVID-19 vaccination (1-3) have recently led to large booster vaccination campaigns. Previous studies showed that basic immunization with two mRNA vaccine doses elicits a robust spike-specific CD8+ T cell response (4-6). The effect of mRNA booster vaccination on the spike-specific CD8+ T cell response remains, however, unclear. Indeed, very little is known about the efficacy, duration and effects on long-term immunity and recall responses in breakthrough infections. In this study, we show that spike-specific CD8+ T cells are immediately and vigorously activated and expanded in all tested individuals after the 3rd and 4th mRNA vaccine shots. However, this CD8+ T cell boost response is characterized by a steep contraction and lasts only for about 30-60 days compared to a prolonged contraction after natural infection. Booster vaccination did not affect long-term spike-specific CD8+ T cell immunity reflected by a stable stem cell memory pool that already reached maximum frequencies after basic immunization. Accordingly, rapid and full-fledged recall responses of boosted spike-specific CD8+ T cells were detectable after breakthrough infection with delta and omicron. Thus, in addition to the previously reported cross-reactivity (7-12) also a robust activation and effector response determines the efficacy of the CD8+ T cell response targeting emerging variants of concern. Neutralizing antibody responses displayed hardly any boost effect towards omicron, further highlighting the relevance of spike-specific CD8+ T cell immunity. In sum, these data will inform future vaccination strategies facing the next COVID-19 wave expected for late 2022/early 2023.

The SARS-CoV-2 variant of concern (VOC) omicron (B1.1.529) is associated with high infectivity and efficient evasion from humoral immunity induced by previous infection or vaccination. In omicron-infected individuals who have been vaccinated or infected before, severe disease seems to be relatively infrequent pointing towards protection by previously primed SARS-CoV-2-specific T cells that cross-recognize omicron. By performing a comprehensive in-depth comparison of the SARS-CoV-2-specific T cell epitope repertoire after natural infection versus after mRNA vaccination, we here demonstrate that spike-derived epitopes are not dominantly targeted in convalescents compared to non-spike epitopes. In vaccinees, however, we detected a broader spike-specific T cell response compared to convalescents reflected by a more diverse repertoire of dominantly targeted spike-specific T cell epitopes. Booster mRNA vaccination induced a broader spike-specific T cell response in convalescents but not in vaccinees with complete initial vaccination. In convalescents and vaccinees, the targeted T cell epitopes are broadly conserved between ancestral and omicron SARS-CoV-2 variants. Hence, our data emphasize the relevance of mRNA vaccine-induced spike-specific CD8+ T cell responses in combating emerging SARS-CoV-2 VOC including omicron and support the benefit of also boosting convalescent individuals with mRNA vaccines.

A specialized and fine-tuned immune response of bats upon infection with viruses is believed to provide the basis for a “friendly” coexistence with these pathogens, which are often lethal for humans and other mammals. First insights into the immunity of bats suggest that bats have evolved to possess their own strategies to cope with viral infections. Yet, the molecular details for this innocuous coexistence remain poorly described and bat infection models are the key to unveiling these secrets. In Jamaican fruit bats (Artibeus jamaicensis), a New World bat species, infection experiments with its (putative) natural viral pathogens Tacaribe virus (TCRV), rabies virus (RABV), and the bat influenza A virus (IAV) H18N11, have contributed to an accurate, though still incomplete, representation of the bat-imposed immunity. Surprisingly, though many aspects of their innate and adaptive immune responses differ from that of the human immune response, such as a contraction of the IFN locus and reduction in the number of immunoglobulin subclasses, variations could also be observed between Jamaican fruit bats and other bat species.

Major histocompatibility complex class II (MHC-II) molecules of multiple species function as cell-entry receptors for the haemagglutinin-like H18 protein of the bat H18N11 influenza A virus, enabling tropism of the viruses in a potentially broad range of vertebrates. However, the function of the neuraminidase-like N11 protein is unknown because it is dispensable for viral infection or the release of H18-pseudotyped viruses. Here, we show that infection of mammalian cells with wild-type H18N11 leads to the emergence of mutant viruses that lack the N11 ectodomain and acquired mutations in H18. An infectious clone of one such mutant virus, designated rP11, appeared to be genetically stable in mice and replicated to higher titres in mice and cell culture compared with wild-type H18N11. In ferrets, rP11 antigen and RNA were detected at low levels in various tissues, including the tonsils, whereas the wild-type virus was not. In Neotropical Jamaican fruit bats, wild-type H18N11 was found in intestinal Peyer’s patches and was shed to high concentrations in rectal samples, resulting in viral transmission to naive contact bats. Notably, rP11 also replicated efficiently in bats; however, only restored full-length N11 viruses were transmissible. Our findings suggest that wild-type H18N11 replicates poorly in mice and ferrets and that N11 is a determinant for viral transmission in bats. Analysis of the genetic stability and replication potential of bat H18N11 influenza A viruses reveals that they are poorly adapted to ferrets and mice and that they transmit among bats only in presence of the full-length neuraminidase-like protein N11.

The human innate immune factor MxA represents an effective interspecies barrier for zoonotic influenza A viruses (IAVs) of animal origin. Accordingly, human but not avian IAVs efficiently escape the antiviral activity of MxA due to adaptive mutations in their viral nucleoprotein. Partial MxA resistance can be acquired in intermediate hosts such as swine, which possess an antivirally active Mx1 protein. Intriguingly, Mx1 of the bat Carollia perspicillata, a host of the recently discovered bat influenza A-like virus H18N11, is antivirally active against avian IAVs, thus raising the question whether H18N11 has undergone a preadaptation to human MxA. Here, by utilizing a chimeric bat influenza virus, PR8-H18N11, we demonstrate that MxA efficiently blocks viral replication in vitro as well as in MxA transgenic mice. Nevertheless, the H18N11 nucleoprotein exhibits partial MxA resistance in a polymerase reconstitution assay, suggesting that a certain degree of MxA preadaptation occurred. Together, our data indicate a currently reduced risk for H18N11 to overcome the human restriction factor MxA. Further adaptive mutations in NP are required to facilitate full MxA escape.

Zoonotic infections of humans with influenza A viruses (IAVs) from animal reservoirs can result in severe disease in individuals and, in rare cases, lead to pandemic outbreaks; this is exemplified by numerous cases of human infection with avian IAVs (AIVs) and the 2009 swine influenza pandemic. In fact, zoonotic transmissions are strongly facilitated by manmade reservoirs that were created through the intensification and industrialization of livestock farming. This can be witnessed by the repeated introduction of IAVs from natural reservoirs of aquatic wild bird metapopulations into swine and poultry, and the accompanied emergence of partially- or fully-adapted human pathogenic viruses. On the other side, human adapted IAV have been (and still are) introduced into livestock by reverse zoonotic transmission. This link to manmade reservoirs was also observed before the 20th century, when horses seemed to have been an important reservoir for IAVs but lost relevance when the populations declined due to increasing industrialization. Therefore, to reduce zoonotic events, it is important to control the spread of IAV within these animal reservoirs, for example with efficient vaccination strategies, but also to critically surveil the different manmade reservoirs to evaluate the emergence of new IAV strains with pandemic potential.

A dysregulated immune response with high levels of SARS-CoV-2 specific IgG antibodies characterizes patients with severe or critical COVID-19. Although a robust IgG response is traditionally considered to be protective, excessive triggering of activating Fc-gamma-receptors (FcγRs) could be detrimental and cause immunopathology. Here, we document that patients who develop soluble circulating IgG immune complexes (sICs) during infection are subject to enhanced immunopathology driven by FcγR activation. Utilizing cell-based reporter systems we provide evidence that sICs are predominantly formed prior to a specific humoral response against SARS-CoV-2. sIC formation, together with increased afucosylation of SARS-CoV-2 specific IgG eventually leads to an enhanced CD16 (FcγRIII) activation of immune cells reaching activation levels comparable active systemic lupus erythematosus (SLE) disease. Our data suggest a vicious cycle of escalating immunopathology driven by an early formation of sICs in predisposed patients. These findings reconcile the seemingly paradoxical findings of high antiviral IgG responses and systemic immune dysregulation in severe COVID-19.Clinical implicationsThe identification of sICs as drivers of an escalating immunopathology in predisposed patients opens new avenues regarding intervention strategies to alleviate critical COVID-19 progression.Graphical abstractA vicious cycle of immunopathology in COVID-19 patients is driven by soluble multimeric immune complexes (sICs). SARS-CoV-2 infection triggers sIC formation in prone individuals. Activation of FcγRIII/CD16 expressing immune cells by sICs precedes a humoral response to SARS-CoV2 infection. sICs and infection add to IgG afucosylation, further enhancing FcγRIII/CD16 activation by opsonized targets. High inflammation induces further sIC mediated immune cell activation ultimately leading to an escalating immunopathology.

SARS-CoV-2, the causative agent of Covid-19, is known to evade the immune system by several mechanisms. This includes the shutdown of the host cellular protein synthesis, which abrogates the induction of antiviral interferon responses. The virus initiates the infection of susceptible cells by binding with its spike protein (S) to the host angiotensin-converting enzyme 2 (ACE2). Here we applied the T cell receptor fusion construct (TRuC) technology to engineer T cells against such infected cells. In our TRuCs an S-binding domain is fused to the CD3ε component of the T cell receptor (TCR) complex, enabling recognition of S-containing cells in an HLA independent manner. This domain either consists of the S-binding part of ACE2 or a single-chain variable fragment of an anti-S antibody. We show that the TRuC T cells are activated by and kill cells that express S of SARS-CoV-2 and its alpha (B.1.1.7) and beta (B.1.351) variants at the cell surface. Treatment of SARS-CoV-2 infected cells with our engineered T cells did not lead to massive cytotoxicity towards the infected cells, but resulted in a complete rescue of the translational shutdown despite ongoing viral replication. Our data show that engineered TRuC T cell products might be used against SARS-CoV-2 by exposing infected cells to the host innate immune system.

SARS-CoV-2 spike mRNA vaccines mediate protection from severe disease as early as 10 days post prime vaccination, when specific antibodies are hardly detectable and still lack neutralizing activity. Vaccine-induced T cells, especially CD8+ T cells, may thus be the main mediators of protection at this early stage. The details of antigen-specific CD8+ T cell induction after prime/boost vaccination, their comparison to naturally induced CD8+ T cell responses and their association with other arms of vaccine-induced adaptive immunity remain, however, incompletely understood. Here, we show on a single epitope level that both, a stable memory precursor pool of spike-specific CD8+ T cells and fully functional spike-specific effector CD8+ T cell populations, are vigorously mobilized as early as one week after prime vaccination when CD4+ T cell and spike-specific antibody responses are still weak and neutralizing antibodies are lacking. Boost vaccination after 3 weeks induced a full-fledged recall expansion generating highly differentiated CD8+ effector T cells, however, neither the functional capacity nor the memory precursor T cell pool was affected. Compared to natural infection, vaccine-induced early memory T cells exhibited similar frequencies and functional capacities but a different subset distribution dominated by effector memory T cells at the expense of self-renewing and multipotent central memory T cells. Our results indicate that spike-specific CD8+ T cells may represent the major correlate of early protection after SARS-CoV-2 mRNA/bnt162b2 prime vaccination that precede other effector arms of vaccine-induced adaptive immunity and are stably maintained after boost vaccination.

SARS-CoV-2 spike mRNA vaccines1–3 mediate protection from severe disease as early as ten days after prime vaccination3, when neutralizing antibodies are hardly detectable4–6. Vaccine-induced CD8+ T cells may therefore be the main mediators of protection at this early stage7,8. The details of their induction, comparison to natural infection, and association with other arms of vaccine-induced immunity remain, however, incompletely understood. Here we show on a single-epitope level that a stable and fully functional CD8+ T cell response is vigorously mobilized one week after prime vaccination with bnt162b2, when circulating CD4+ T cells and neutralizing antibodies are still weakly detectable. Boost vaccination induced a robust expansion that generated highly differentiated effector CD8+ T cells; however, neither the functional capacity nor the memory precursor T cell pool was affected. Compared with natural infection, vaccine-induced early memory T cells exhibited similar functional capacities but a different subset distribution. Our results indicate that CD8+ T cells are important effector cells, are expanded in the early protection window after prime vaccination, precede maturation of other effector arms of vaccine-induced immunity and are stably maintained after boost vaccination., Longitudinal analyses of SARS-CoV-2 mRNA vaccine-elicited epitope-specific CD8+ T cell responses shows that CD8+ T cells are rapidly induced after prime vaccination and stably maintained after boost vaccination.

Key Points Question What is the rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and the seroprevalence of SARS-CoV-2 antibodies in children aged 1 to 10 years and a corresponding parent in a population-based sample in southwest Germany? Findings This large-scale, multicenter, cross-sectional investigation of 4964 participants accurately determined anti–SARS-CoV-2 seropositivity by combining the results of enzyme-linked immunosorbent assay and immunofluorescence tests. The estimated SARS-CoV-2 seroprevalence was low in parents (1.8%) and 3-fold lower in children (0.6%). Meaning The low seroprevalence of SARS-CoV-2 antibodies in young children in this study may indicate that they do not play a key role in SARS-CoV-2 spreading during the current pandemic., This cross-sectional investigation conducted in southwest Germany describes the rate of severe acute respiratory syndrome coronavirus 2 infections and the seroprevalence of antibodies in children aged 1 to 10 years, compared with a parent of each child, in a population-based sample., Importance School and daycare closures were enforced as measures to confine the novel coronavirus disease 2019 (COVID-19) pandemic, based on the assumption that young children may play a key role in severe acute respiratory coronavirus 2 (SARS-CoV-2) spread. Given the grave consequences of contact restrictions for children, a better understanding of their contribution to the COVID-19 pandemic is of great importance. Objective To describe the rate of SARS-CoV-2 infections and the seroprevalence of SARS-CoV-2 antibodies in children aged 1 to 10 years, compared with a corresponding parent of each child, in a population-based sample. Design, Setting, and Participants This large-scale, multicenter, cross-sectional investigation (the COVID-19 BaWü study) enrolled children aged 1 to 10 years and a corresponding parent between April 22 and May 15, 2020, in southwest Germany. Exposures Potential exposure to SARS-CoV-2. Main Outcomes and Measures The main outcomes were infection and seroprevalence of SARS-CoV-2. Participants were tested for SARS-CoV-2 RNA from nasopharyngeal swabs by reverse transcription–polymerase chain reaction and SARS-CoV-2 specific IgG antibodies in serum by enzyme-linked immunosorbent assays and immunofluorescence tests. Discordant results were clarified by electrochemiluminescence immunoassays, a second enzyme-linked immunosorbent assay, or an in-house Luminex-based assay. Results This study included 4964 participants: 2482 children (median age, 6 [range, 1-10] years; 1265 boys [51.0%]) and 2482 parents (median age, 40 [range, 23-66] years; 615 men [24.8%]). Two participants (0.04%) tested positive for SARS-CoV-2 RNA. The estimated SARS-CoV-2 seroprevalence was low in parents (1.8% [95% CI, 1.2–2.4%]) and 3-fold lower in children (0.6% [95% CI, 0.3-1.0%]). Among 56 families with at least 1 child or parent with seropositivity, the combination of a parent with seropositivity and a corresponding child with seronegativity was 4.3 (95% CI, 1.19-15.52) times higher than the combination of a parent who was seronegative and a corresponding child with seropositivity. We observed virus-neutralizing activity for 66 of 70 IgG-positive serum samples (94.3%). Conclusions and Relevance In this cross-sectional study, the spread of SARS-CoV-2 infection during a period of lockdown in southwest Germany was particularly low in children aged 1 to 10 years. Accordingly, it is unlikely that children have boosted the pandemic. This SARS-CoV-2 prevalence study, which appears to be the largest focusing on children, is instructive for how ad hoc mass testing provides the basis for rational political decision-making in a pandemic.

Small RNA viruses only have a very limited coding capacity, thus most viral proteins have evolved to fulfill multiple functions. The highly conserved matrix protein 1 (M1) of influenza A viruses is a prime example for such a multifunctional protein, as it acts as a master regulator of virus replication whose different functions have to be tightly regulated. The underlying mechanisms, however, are still incompletely understood. Increasing evidence points towards an involvement of posttranslational modifications in the spatio-temporal regulation of M1 functions. Here, we analyzed the role of M1 tyrosine phosphorylation in genuine infection by using recombinant viruses expressing M1 phosphomutants. Presence of M1 Y132A led to significantly decreased viral replication compared to wildtype and M1 Y10F. Characterization of phosphorylation dynamics by mass spectrometry revealed the presence of Y132 phosphorylation in M1 incorporated into virions that is most likely mediated by membrane-associated Janus kinases late upon infection. Molecular dynamics simulations unraveled a potential phosphorylation-induced exposure of the positively charged linker domain between helices 4 and 5, supposably acting as interaction platform during viral assembly. Consistently, M1 Y132A showed a defect in lipid raft localization due to reduced interaction with viral HA protein resulting in a diminished structural stability of viral progeny and the formation of filamentous particles. Importantly, reduced M1-RNA binding affinity resulted in an inefficient viral genome incorporation and the production of non-infectious virions that interferes with virus pathogenicity in mice. This study advances our understanding of the importance of dynamic phosphorylation as a so far underestimated level of regulation of multifunctional viral proteins and emphasizes the potential feasibility of targeting posttranslational modifications of M1 as a novel antiviral intervention., Author summary Due to limited genome capacity, viral proteins often fulfill multiple functions during viral replication. Matrix proteins of enveloped viruses have to be intrinsically multifunctional, since they confer integrity of the virion, but also function in disintegration during virus entry. The highly conserved influenza A virus matrix protein 1 (M1) is a prototype for such a multifunctional protein, however, the underlying mechanisms that regulate its functional switches are only scarcely understood. Here, we unraveled M1 phosphorylation at tyrosine 132 as a spatio-temporal regulatory mechanism that potentially induces structural diversification and is needed for efficient viral genome incorporation during assembly. The site is most likely phosphorylated by cellular membrane-associated Janus kinases late in infection, suggesting that these kinases might serve as novel cellular targets for antiviral intervention.

In 2012 and 2013, influenza virus genome sequences of two new influenza A virus (IAV) subtypes were discovered in bat specimens, but further characterization was largely impeded by the lack of infectious virus. With the identification of highly susceptible cell lines, reconstitution of infectious bat IAV by reverse genetics recently succeeded and allowed a first insight into the life cycle of these viruses. Although there is a certain degree of functional compatibility between bat and conventional influenza A virus proteins, there are striking differences, including receptor usage, polarity of infection and reassortment potential.

In 2012 and 2013, the genomic sequences of two novel influenza A virus (IAV) subtypes, designated H17N10 and H18N11, were identified via next-generation sequencing in the feces of the little yellow-shouldered fruit bat (Sturnira lilium) and the flat-faced fruit-eating bat (Artibeus planirostris), respectively. The pathogenesis caused by these viruses in their respective host species is currently insufficiently understood, which is primarily due to the inability to obtain and keep these bat species under appropriate environmental and biosafety conditions. Seba&rsquo, s short-tailed bats (Carollia perspicillata), in contrast, are close relatives and a natural H18N11 reservoir species, with the advantage of established animal husbandry conditions in academic research. To study viral pathogenesis in more detail, we here oro-nasally inoculated Seba&rsquo, s short-tailed bats with the bat IAV H18N11 subtype. Following inoculation, bats appeared clinically healthy, but the histologic examination of tissues revealed a mild necrotizing rhinitis. Consistently, IAV-matrix protein and H18-RNA positive cells were seen in lesioned respiratory and olfactory nasal epithelia, as well as in intestinal tissues. A RT-qPCR analysis confirmed viral replication in the conchae and intestines as well as the presence of viral RNA in the excreted feces, without horizontal transmission to na&iuml, ve contact animals. Moreover, all inoculated animals seroconverted with low titers of neutralizing antibodies.

Zoonotic influenza A viruses of avian origin can cause severe disease in individuals, or even global pandemics, and thus pose a threat to human populations. Waterfowl and shorebirds are believed to be the reservoir for all influenza A viruses, but this has recently been challenged by the identification of novel influenza A viruses in bats1,2. The major bat influenza A virus envelope glycoprotein, haemagglutinin, does not bind the canonical influenza A virus receptor, sialic acid or any other glycan1,3,4, despite its high sequence and structural homology with conventional haemagglutinins. This functionally uncharacterized plasticity of the bat influenza A virus haemagglutinin means the tropism and zoonotic potential of these viruses has not been fully determined. Here we show, using transcriptomic profiling of susceptible versus non-susceptible cells in combination with genome-wide CRISPR-Cas9 screening, that the major histocompatibility complex class II (MHC-II) human leukocyte antigen DR isotype (HLA-DR) is an essential entry determinant for bat influenza A viruses. Genetic ablation of the HLA-DR α-chain rendered cells resistant to infection by bat influenza A virus, whereas ectopic expression of the HLA-DR complex in non-susceptible cells conferred susceptibility. Expression of MHC-II from different bat species, pigs, mice or chickens also conferred susceptibility to infection. Notably, the infection of mice with bat influenza A virus resulted in robust virus replication in the upper respiratory tract, whereas mice deficient for MHC-II were resistant. Collectively, our data identify MHC-II as a crucial entry mediator for bat influenza A viruses in multiple species, which permits a broad vertebrate tropism.

Lysine acetylation is a post-translational modification known to regulate protein functions. Here we identify several acetylation sites of the influenza A virus nucleoprotein (NP), including the lysine residues K77, K113 and K229. Viral growth of mutant virus encoding K229R, mimicking a non-acetylated NP lysine residue, is severely impaired compared to wildtype or the mutant viruses encoding K77R or K113R. This attenuation is not the result of decreased polymerase activity, altered protein expression or disordered vRNP co-segregation but rather caused by impaired particle release. Interestingly, release deficiency is also observed mimicking constant acetylation at this site (K229Q), whereas virus encoding NP-K113Q could not be generated. However, mimicking NP hyper-acetylation at K77 and K229 severely diminishes viral polymerase activity, while mimicking NP hypo-acetylation at these sites has no effect on viral replication. These results suggest that NP acetylation at K77, K113 and K229 impacts multiple steps in viral replication of influenza A viruses., Post-translational modifications of influenza A virus proteins can regulate virus replication, but the effect of nucleoprotein (NP) acetylation is not known. Here, Giese et al. identify four NP lysine residues that are acetylated in infected cells and study their role in polymerase activity and virion release.

Influenza A viruses (IAVs) originating from aquatic waterfowl recurrently cross interspecies barriers, which is greatly facilitated by utilizing cell surface-exposed monosaccharide sialic acids located on vertebrate cells as a universal host cell receptor. These glycan structures are first bound by the viral hemagglutinin (HA) for cell entry and then cleaved by the viral neuraminidase (NA) for particle release. In contrast, viruses of the recently identified bat-borne IAV subtypes H17N10 and H18N11 encode HA and NA homologs unable to interact with sialic acid residues despite a high degree of structural homology with their conventional counterparts. However, the most recent findings show that bat IAV HAs make use of the major histocompatibility complex class II proteins of different vertebrate species to gain entry into host cells, potentially permitting a broader host tropism. This review recapitulates current progress in the field of bat IAV research including the first assessment of the spillover potential of these bat viruses into other mammals.