Emerging Microbes & Infections

Since 2020, highly pathogenic avian influenza (HPAI) A(H5Nx) clade 2.3.4.4b viruses have spread globally, causing extensive outbreaks in domestic and wild birds. Increased circulation has resulted in frequent spillover to mammals, and occasional mammal-to-mammal transmission. Although human infections remain rare, the zoonotic potential of these viruses continues to be a public health concern. We investigated six cases of HPAI in red foxes (Vulpes vulpes) in Norway during 2022-2024 and identified infections with H5N1 and H5N5 viruses. Pathological and virological investigations demonstrated systemic infection, with prominent lesions in the brain and/or lungs. Phylogenetic analyses showed high similarity between viruses detected in foxes and those concurrently circulating in wild birds. The mammalian adaptation marker PB2:E627K was identified in one H5N1 virus and as a minority variant in a second H5N1 virus.

SARS-CoV-2 continues to circulate globally at high levels and to evolve into new variants. Recently, a new saltation variant harbouring a highly mutated spike protein, PJ.2.1, emerged in North America. Here, we provide a brief epidemiological and virological characterization of PJ.2.1 and cocirculating variants. We report that PJ.2.1 is spreading in the USA, Canada, and Spain and mainly infects individuals aged 60 years and older, as do most other variants, with the exception of BA.3.2, which preferentially infects individuals aged 0-9 years. PJ.2.1 was less susceptible to inhibition by an antibody against ACE2 than were the other variants, indicating increased ACE2 binding. In contrast, PJ.2.1 did not show augmented evasion of antibodies from vaccinees who had received the LP.8.1-adapted vaccine compared with most other variants analysed. These results suggest that augmented ACE2 affinity rather than increased antibody evasion might drive the current, rapid spread of PJ.2.1.

Mosquito-borne orthoflaviviruses pose a significant threat to human and animal health worldwide. In Europe, West Nile (WNV), Usutu (USUV) and Bagaza (BAGV) viruses have expanded their geographic distribution and are detected with increasing frequency. Following the emergence of BAGV in 2021, we investigated the circulation dynamics and genomic diversity of orthoflaviviruses in southern Portugal, where their epidemiology remains poorly understood. Active Orthoflavivirus surveillance was conducted in birds and mosquitoes during 2021-2023 using serological and molecular assays, complemented by viral genome sequencing and phylogenomic analyses. Viral RNA was detected in 3.5% (41/1,171) of birds, while seroneutralization assays identified an overall seroprevalence of 55.3% (503/910). WNV RNA (lineage-1, strains WMed-1.2 and WMed-1.3) was detected annually in resident birds, including Alectoris rufa, Cyanopica cooki and Garrulus glandarius (1.5%, 18/1,171), and in Culex univittatus mosquitoes (0.8%, 2/255). Together with a WNV-specific seroprevalence of 28.5% (259/910) in birds, these findings support sustained local circulation. USUV RNA (Africa 3.1 sub-lineage) was detected in A. rufa in 2021 and 2023 (0.2%, 2/1,171), but seroprevalence was low (1.3%, 8/623), consistent with intermittent circulation. BAGV RNA (genotype-2) was detected only during the 2021 outbreak in A. rufa and Emberiza calandra (1.8%, 21/1,171), although BAGV-specific antibodies (6.6%, 60/910) were detected for up to two years after the outbreak, suggesting continued exposure or low-level circulation. Overall, our findings reveal contrasting circulation dynamics of orthoflaviviruses in southern Portugal. Sustained WNV circulation implies the need to strengthen avian and human surveillance in Portugal to better assess its public health risk, while the sporadic detection of USUV and BAGV underscores the value of long-term, integrated One Health surveillance for improving early warning and preparedness for emerging mosquito-borne diseases.

Since emerging in 2020, clade 2.3.4.4b H5N1 high pathogenicity avian influenza virus (HPAIV) has disseminated globally, causing substantial infection and mortality in wild birds and poultry. Additionally, numerous spill-over events into mammals have occurred, including mass mortalities and sporadic human infections. Such events can drive the acquisition of mammalian-adaptive mutations, which further increase the risk to humans; the most well characterised mutation is the glutamate to lysine change at amino acid position 627 in the polymerase basic 2 protein (PB2-627K). Across avian influenza viruses, PB2-627K enhances polymerase activity and replication in mammalian cells, increasing zoonotic and pandemic potential. However, bioinformatic analyses indicate that PB2-627K remains rare among clade 2.3.4.4b H5N1 viruses circulating in avian populations. Here, we investigated the impact of PB2-627K on viral fitness in avian hosts to assess the potential for mammalian-adapted viruses to re-establish in birds, mimicking infection of avian species following scavenging on mammalian species where PB2-627K has already emerged. Using a representative H5N1 virus (European genotype AB), PB2-627K increased polymerase activity and replication in human cells without compromising replication in avian cells. A mammalian-derived PB2-627K H5N1 isolate from a fox exhibited comparable replication kinetics and transmission efficiency in chickens and ducks to a closely related PB2-627E virus. Notably, PB2-627K remained genetically stable at consensus level following infection and transmission in both avian hosts. These findings demonstrate that mammalian-adaptive mutations acquired during spill-over can be maintained in avian populations, potentially elevating zoonotic risk and underscoring the importance of surveillance for such mutations in birds.

Recent zoonotic coronavirus outbreaks have sparked an interest in understanding coronaviruses circulating in animal reservoirs. While bats are recognised as major reservoirs for these viruses, coronaviruses have also been detected in a wide range of terrestrial small mammals, particularly rodents. However, coronavirus diversity in these mammals, specifically in Europe, is still poorly characterised. In this study, we detected and characterised coronaviruses in terrestrial small mammals and bats from Belgium, France, Germany, and Ireland. We screened tissue samples from rodents and shrews and environmental bat guano using pan-coronavirus real-time and conventional PCRs, with positive results confirmed by sanger sequencing. Among 2667 bat and 1152 terrestrial mammal samples, we detected 59 positive samples, 36 from bats and 23 from rodents, from which we recovered 60 coronavirus sequences, spanning both Alphacoronavirus and Betacoronavirus lineages. Through next generation sequencing we identified one Pipistrellus pygmaeus bat guano sample carrying two distinct alphacoronaviruses, representing Nyctacovirus and Pedacovirus subgenera. Among rodents, most coronavirus-positive samples originated from a zoo in Belgium, where several CoV lineages co-circulated. The identified rodent coronaviruses clustered among previously described rodent-associated lineages, some of which also include human and other mammal-derived coronavirus sequences. Consistent with previous studies, we found sarbecoviruses in horseshoe bats (particularly Rhinolophus ferrumequinum and R. hipposideros) and merbecoviruses in Plecotus auritus bats, and these viruses are distantly related to the human coronaviruses of the respective families. Similar to bat coronaviruses, some rodent coronaviruses strains seemed to be association with specific rodent species. In conclusion, our study enhances the understanding of coronaviruses in rodents and bats, revealing potential hotspots for these viruses and their implication for human and animal health. These findings underscore the necessity for continued surveillance of coronaviruses in wildlife reservoirs to mitigate future zoonotic spillover risks.

Swine Influenza A virus (swIAV) poses constant health threat for both humans and animals. This study comprehensively analysed the genetic diversity and evolution of European swIAVs from 2013 to 2022. To address existing classification gaps, an easily accessible full-genome genotyping tool based on Nextclade was developed alongside a global nomenclature system. Application of this tool to European sequence data revealed unprecedented genetic diversity, successfully identifying 150 swIAV genotypes mixing segments of both swine and human origin. Bayesian phylogeographic models, combined with economic data, identified that the trade of live weaner pigs for fattening drove the transboundary spread of swIAVs across Europe. The study detected repeated human-to-swine reverse-zoonotic events across multiple European countries. These findings clearly highlight the role of commercial pig movements in viral dissemination and emphasize the critical importance of harmonized genomic surveillance to monitor swIAV viral evolution to inform global pre-pandemic preparedness strategies.

Low pathogenic avian influenza A(H7N7) virus detected in a poultry worker in Taiwan, 2026 was related to viruses circulating in Asian wild birds and possessed PB2 E627K, a mammalian adaptation marker. Enhanced surveillance for H7 viruses in poultry and rapid characterization of human cases are essential to assess pandemic potential.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging, tick-borne zoonosis caused by severe fever with thrombocytopenia syndrome virus (SFTSV) and is associated with high case-fatality rates in humans and cats. No vaccines or antiviral drugs are currently available for the prevention or treatment of feline SFTS. Because cats with SFTS often develop blood viral RNA loads exceeding those in severe human cases, we hypothesized that some naturally recovered cats develop strong neutralizing antibody responses and may serve as a potential source of antibody-rich serum for passive immunotherapy. We compared 80% plaque-reduction neutralization test (PRNT80) titers in convalescent sera from six human SFTS survivors and 14 cats that had recovered from naturally acquired SFTS, then evaluated the therapeutic efficacy of convalescent cat serum in SFTSV-infected, interferon receptor-deficient AG129 mice. Some SFTS-recovered cats showed high PRNT80 titers. Passive administration of high-titer convalescent cat serum early after infection protected SFTSV-infected mice. A single dose given at 2 or 3 days post-infection completely protected mice, whereas treatment at 4 days post-infection resulted in 40% survival. Administration on two consecutive days was associated with lower late-phase viremia in surviving mice. Sera from three independent SFTS-recovered cats improved survival, with greater effects observed for sera with higher neutralizing antibody titers. These findings indicate that some cats recovering from SFTS can develop high neutralizing antibody titers and their sera can exert therapeutic effects in an SFTSV-infected mouse model. These findings support further evaluation of passive immunotherapy as a treatment strategy for feline SFTS.

Background. Influenza remains a major cause of global morbidity and mortality. Pharmacodynamic biomarkers that quantify treatment response within the lung could accelerate influenza therapeutic development. We evaluated [18F]-fluorodeoxyglucose positron emission tomography ([18F]-FDG-PET) as a non-invasive biomarker of antiviral efficacy. Methods. Serial [18F]-FDG-PET was evaluated in two murine H1N1 influenza models using mouse-adapted PR8 strain and CA-09 clinical isolate following treatment with favipiravir, baloxavir marboxil, or ribavirin. PET measures were compared with pulmonary viral burden, inflammatory cytokine expression, computed tomography (CT) imaging, and respiratory function measured by whole-body plethysmography (WBP). Results. Antiviral treatment in PR8 infection model reduced lung [18F]-FDG uptake by 27-49% and metabolic lung volume (MLV) by 40.5-74.6% (both p < 0.001). Antiviral response was detectable as early as 3 days post-infection, when uptake decreased by 28.7-53.2% and MLV by 33.8-75.0%. Lung uptake also strongly correlated with MLV (r = 0.93, p < 0.001) and with pulmonary viral burden and inflammatory mediators. These findings were reproduced in a model of pandemic H1N1/CA-09, where baloxavir reduced uptake by 37.4% (p = 0.02) and MLV by 67.5% (p < 0.001) at day 3. In both models, changes in [18F]-FDG-PET parameters preceded improvements in lung CT and respiratory function. Conclusions. Lung [18F]-FDG-PET provides an early, quantitative measure of antiviral response in experimental influenza, supporting its further evaluation as a translational pharmacodynamic endpoint.

Infectious bronchitis virus (IBV) is an economically important avian gammacoronavirus. IBV uses sialic acids and heparan sulfate for cellular attachment, but the host proteins governing its infection remain poorly defined. Here, we investigated the roles of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) during IBV Beaudette (IBV BD) infection. ACE2 knockout impaired IBV replication in DF-1 cells, whereas ACE2 reconstitution restored infection. Furthermore, ACE2 overexpression enhanced infection of DF-1 and primary chicken embryo kidney cells, supporting the role of chicken ACE2 as a proviral host factor. In contrast, TMPRSS2 exerted a restrictive function on IBV BD infection as demonstrated in TMPRSS2 KO DF-1 cells and upon pharmacological inhibition, which significantly increased IBV BD infection in DF-1 and Vero cells. RNA sequencing revealed significant changes in lipid metabolism and membrane-related processes following TMPRSS2 knockout and pharmacological inhibition. These findings highlight the opposing roles of ACE2 and TMPRSS2 in IBV BD infection, emphasizing the combined impact of proviral host factors, protease activity, and the cellular membrane environment during gammacoronavirus infections.

The emergence of a dominant poultry-associated strain of Campylobacter jejuni in New Zealand coincided with a multi-year epidemic of human campylobacteriosis. This was characterised by an increase in cases to 2006, when one of the highest national case-rates in the world was recorded, followed by a rapid decline attributed to interventions in the poultry industry. The strain belonged to an internationally rare multilocus sequence type, ST474 - a member of Clonal Complex (CC) 48 - that was highly prevalent in both poultry and human cases in New Zealand but was also identified in other samples. ST474 isolates from humans, animal reservoirs and environmental water samples were collected between 2005 and 2019 and whole genome sequenced (N=443). Isolates from a 2018/9 case-control study of campylobacteriosis in New Zealand were included for genomic comparisons with other sequence types and CCs. This presented an opportunity to examine the genomic epidemiology of a single, relatively recently emerged lineage of C. jejuni, and improve our understanding of drivers of emergence and persistence in a relatively isolated ecosystem. Six subpopulations (clades) of ST474 were identified and these varied in terms of their host association, persistence, patterns of homologous recombination, and complement of mobile genetic elements, including plasmids and chromosomally integrated elements. Clade E was associated with a single poultry supplier in the initial epidemic phase and accounted for 34.5% of human cases. Clade F emerged from a declining Clade E after the peak in human cases and was also associated with poultry. The emergence of Clade F was accompanied by the loss of integrated element CJIE5 and the acquisition of multiple blocks of recombination, likely from diverse ancestral C. jejuni lineages, and the loss of the methionine biosynthesis operon metAB. In contrast, Clades A-D were detected at low frequencies in human cases over the 14-year period of surveillance and were associated with multiple hosts. This longitudinal study sheds light on the evolutionary processes that result in strain emergence and differentiation, highlighting the role of horizontal gene transfer in the evolution and adaptation of this pathogen to new niches, and the subsequent impact on public health.

Porcine epidemic diarrhea virus (PEDV) was introduced into the United States (USA) in 2013 and has circulated ever since. PEDV causes significant losses in the swine industry, with the greatest impact observed during the first years following its introduction into the country. However, the evolutionary dynamics of the virus remain underexplored. Recently, analyses of the Spike protein subunit S1 suggested that the PEDV population currently circulating in the USA represents a fraction of its historical diversity and comprises only two clades restricted to specific geographic regions. These observations were based on a limited set of S1 sequences. Furthermore, our understanding of evolutionary dynamics at the genomic level is even more limited, as complete PEDV genomes have not been generated since 2017. Here, we characterized the evolutionary dynamics of PEDV populations in the USA using complete genomes and assessed the contribution of different evolutionary mechanisms to shaping population structure. We analyzed 338 complete genomes, of which 25 were obtained in this study, together with 623 Spike S1 sequences, of which 41 were obtained in this study. All sequences obtained in this study were assigned to the non-S-INDEL strain. No S-INDEL sequences were recovered in this study, although these viruses continue to circulate in the country. Our analyses revealed that most sequences sampled after 2023 formed a monophyletic clade divergent from sequences collected in previous years, suggesting an ongoing temporal population structuring. Population structure analyses further supported evidence of population differentiation over time. Recombination analyses indicated that sequences belonging to the contemporary clade shared a single recombination event, suggesting that this clade may have emerged through recombination. Time-scaled S1 phylogenies were consistent with previous findings, supporting the circulation of only two contemporary clades; however, one of these clades was detected for the first time outside its previously reported geographic range. Our findings document temporal genetic differentiation in US PEDV populations, consistent with continued viral evolution, and broaden the known geographic distribution of contemporary S1 clades. These results highlight the value of continued genomic surveillance to monitor changes in PEDV diversity and distribution and provide sequence data to inform vaccine research.

Background: A large increase in mortality from severe acute respiratory infections (SARI) in Brazil in 2025 was mainly driven by influenza A and respiratory syncytial virus (RSV) among children and the aged, but 2026 data remain largely unpublished. Methods: Secondary data on SARI by age group (<2, 2-4, 5-14, 15-49, 50-64, 65+ years) and virus (Influenza A/B, RSV, SARS-CoV-2, adenovirus, rhinovirus, bocavirus, and metapneumovirus) were retrieved for 35 weeks of 2026. Weekly variations in infection rate (IR) and mortality rate (MR) were described by virus and age group. Case fatality ratio (CFR) and vaccine-preventable deaths from influenza, RSV, and SARS-CoV-2 were analysed by age group. Missing virus classification was estimated by multinomial regression. Poisson-based 95% confidence intervals (CI) were calculated for MR. Results: Influenza A infections quintupled during February and March, with a mortality peak in April, mainly due to H2N3. RSV and rhinovirus caused more deaths than influenza viruses, especially among young children (<2) and the aged (65+). The former were most frequently infected by RSV and the latter by rhinovirus. For those 50 years or older, influenza B reached a CFR of about 20%, compared with 5-15% for influenza A, metapneumovirus, rhinovirus, and other non-subtyped viruses. The highest vaccine-preventable MRs per 100,000 were 17.23 for the oldest and 8.62 for the youngest. Under ideal conditions, 6418 lives could have been saved, about half among children and adolescents <15 years old. Conclusions: Vaccine-preventable SARI in Brazil exerted a high toll in fall and winter 2026, mainly due to influenza A, RSV, and rhinovirus. Better vaccine coverage may significantly reduce this toll.

Porcine deltacoronavirus (PDCoV) is a globally circulating coronavirus of swine that causes severe enteric disease and mortality in neonatal piglets. Its broad host range and zoonotic potential raises concerns about continued spillover into human populations. However, the host factors that govern PDCoV infection remain largely unexplored. Identifying host factors involved in virus infection may uncover novel therapeutic targets for antiviral drug development or targets for gene editing to create resistant pigs. Here, we conducted a genome-wide CRISPR knockout (GeCKO) screen to identify host factors contributing to PDCoV infection in swine testicular (ST) cells. Small guide RNAs (sgRNAs) targeting the ANPEP gene, expressing the main receptor porcine aminopeptidase N for PDCoV, were enriched in PDCoV-resistant cells, demonstrating the validity of the screen. Moreover, we identified transmembrane protein 30A (TMEM30A), an accessory {beta}-subunit of the P4-ATPase flippase complex, as a host dependency factor for PDCoV infection along with several potential PDCoV-induced cell death regulators, including DET1, IFNAR1, RFWD2, STAT1 and TP53. We further demonstrated that PDCoV attachment and internalization into cells were significantly impaired in TMEM30A knockout ST cells, suggesting that TMEM30A is important in the early stages of the PDCoV life cycle. Because TMEM30A also contributes to SARS-CoV-2 replication, future studies are warranted to investigate its mechanistic role in the context of coronavirus infection.

Phenuiviruses which include Rift Valley Fever Virus (RVFV), classified by WHO as one of the top priority pathogens with outbreak potential, are emerging arthropod-borne viruses that pose an increasing threat to public health. In line with the prototype pathogen framework advanced by the NIAID, the sandfly-transmitted Toscana virus (TOSV) has been adopted as a prototype to advance understanding of relevant phenuiviruses and inform the development of broadly applicable medical countermeasures. In this study, we sought to isolate and characterize monoclonal antibodies (mAbs) elicited by natural TOSV infection to identify shared antigenic determinants. By employing the conserved envelope Gc glycoprotein as bait for antigen-specific B cell sorting, we recovered more than 1,450 memory B cells and identified 112 Gc-specific neutralizing mAbs. Over one-third of these mAbs exhibited cross-reactivity with RVFV, a genetically distinct phenuivirus. Selected mAbs provided prophylactic protection in a murine model of TOSV infection. Together, our findings establish Gc as an important target of protective neutralizing antibodies and provide insights that may guide the rational design of widely effective interventions, strengthening readiness against future phenuivirus outbreaks.

Background: More than five years after the COVID-19 outbreak, the infection by the SARS-CoV-2 virus should still be considered as a global threat with highly heterogeneous clinical outcomes from asymptomatic to fatal depending on existing genetic and phenotypic inter-individual and inter-population variability. Our objective is to identify risk loci associated with COVID-19 in an admixed Latin American population. Methods: We performed a genome-wide association study in the framework of the Chilean C19-GenoNet team, analyzing a cohort of 3,417 individuals recruited from the northernmost to the southernmost regions of the country, who presented variations in the severity of their COVID-19 clinical manifestations. Results: Our investigation replicated the extensively reported association of several variants at the 3p21.31 locus with COVID-19 severity and found a suggestive association for a variant within the FOXP4 gene at 6p21.1 with COVID-19 hospitalization. Both associations appear to be shared with other populations. Importantly, our study identified three previously unreported loci associated with COVID-19 severity or hospitalization at 7q21.11, 16p13.12 and 6p25.3, and one additional locus at 4p13 associated with SARS-CoV-2 positivity, a proxy for infection susceptibility. Conclusions: these new risk loci may represent population-specific effects in Chilean and, potentially, other Latin American admixed groups. Our study highlights the importance of expanding efforts to study underrepresented and genetically different populations, which may provide new clues on the genetic basis of human diseases and may help to anticipate global responses to emerging viral infections and future pandemics.

The 2026 Andes virus (ANDV) outbreak aboard the MV Hondius cruise ship resulted in 11 confirmed cases and 3 deaths and raised questions regarding the origin of infection, with much media focus resting on a landfill in Tierra del Fuego. We evaluated competing exposure hypotheses by assembling open data on reservoir host occurrences, rodent serosurveys, and historical ANDV outbreaks along with the index case's self-documented, publicly-posted citizen-science digital record of their movements. Historical outbreaks associated with human-to-human transmission were concentrated within a restricted region spanning southern Chile and adjacent western Argentina, coinciding with the distribution of the principal reservoir host, Oligoryzomys longicaudatus, and areas identified as elevated risk by multiple ecological and genetic models. The index case was documented within this transmission focus shortly before the putative exposure period. Together, our open data approach was able to rapidly locate initial exposure within the established ANDV transmission focus and develop scenarios to prioritise further epidemiological investigation.

Powassan virus (POWV) is an emerging tick-borne orthoflavivirus that causes severe encephalitis, long-term neurologic sequelae, and death, yet no approved antiviral therapies exist. Here, we evaluated several previously characterized nucleoside analogs as candidate countermeasures for POWV encephalitis. Favipiravir, molnupiravir, 4'-fluorouridine (4'-FlU), and GS-441524 inhibited POWV replication in vitro and demonstrated comparable activity against West Nile virus (WNV). We established C3H/HeNCrl mice as a stringent POWV disease model, showing increased susceptibility, higher day 7 brain titers, and more pronounced neurologic signs resembling severe human disease, compared with C57BL/6 mice. In prophylactic and therapeutic studies, 4'-fluorouridine was the most efficacious compound tested, significantly reducing brain viral burden even when treatment was delayed. Direct comparison with molnupiravir, favipiravir, and GS-441524 in mice confirmed superior survival benefit and antiviral activity for 4'-FlU against both POWV and WNV. These data identify 4'-fluorouridine as a promising therapeutic candidate for neurotropic flavivirus disease.

Protein kinase CK2 (CK2), a ubiquitously expressed serine/threonine kinase, has emerged as a key host factor exploited by several viruses, including Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we investigate the role of CK2 subunits in SARS-CoV-2 replication and evaluate the antiviral potential and broad-spectrum anti-coronavirus activity of two CK2 inhibitors: the previously described ATP-competitive inhibitor CX-4945 and a newly developed, highly selective bivalent inhibitor, AB668. The siRNA-mediated knockdown of CK2 subunits significantly reduced SARS-CoV-2 replication, highlighting its essential role in the viral lifecycle. Co-immunoprecipitation assays revealed that the SARS-CoV-2 nucleoprotein interacts with CK2. Furthermore, bio-layer interferometry assays demonstrated that the nucleoprotein specifically binds to the tetrameric CK2 holoenzyme (CK22{beta}2) but not to individual CK2 or CK2{beta} subunits. Pharmacological inhibition of CK2 with AB668 exhibited potent antiviral activity, significantly reducing viral replication by targeting a pre-replicative or RNA-replicative step of the viral life cycle. Importantly, AB668 displayed broad-spectrum antiviral activity, effectively inhibiting both HCoV-OC43 ({beta}-CoV) and HCoV-229E (-CoV). In summary, our findings establish CK2 as a critical host factor for SARS-CoV-2 replication and identify AB668 as a promising candidate for broad-spectrum antiviral therapy. With its high selectivity, minimized off-target effects, and efficacy against multiple coronaviruses, AB668 represents a valuable chemobiological and therapeutic tool.

Kaposi's sarcoma-associated herpesvirus (KSHV) is a human tumor virus. Common marmosets, a potential non-human primate model for vaccine development and infection studies, have previously been shown to support KSHV infection. We established infection of marmosets with BAC-derived, recombinant KSHV to analyze the role of individual glycoproteins (GPs) in tissue tropism. Three groups of four animals were infected intravenously with BAC-derived KSHV wild type (wt), EphA2-receptor-binding-deficient KSHV gHASAELAAN, or KSHV{triangleup}K8.1, lacking glycoprotein K8.1. Viral DNA was detected in multiple tissues of all animals, with the highest loads in spleen, liver, heart, and bone marrow. In most tissues, viral DNA loads did not significantly differ between groups. However, KSHV{triangleup}K8.1-infected animals exhibited significantly lower KSHV DNA levels in liver and bone marrow. KSHV wt infection induced activation of CD4+ and CD8+ T-cells. In animals infected with KSHV wt, KSHV gHASAELAAN or KSHV{triangleup}K8.1, different B cell subpopulations expanded after infection, which suggests that the glycoproteins themselves or the cell tropism imparted by their presence or absence might shape the host response to KSHV. In summary, our findings demonstrate that neither the Eph receptor interaction nor GP K8.1 is essential for intravenous infection, but K8.1 critically contributes to KSHV tissue tropism in vivo.