Biology subjects

Shepard, J. D.

Publications and source records attributed to Shepard, J. D..

4 recordsLinked to original sources

bioRxiv2026

Contemporary Victoria and Yamagata Influenza B Viruses Elicit Lineage-Specific Differences in Innate Immunity

The two influenza B virus (FLUBV) lineages, Victoria and Yamagata, have continued to diverge since their separation in the 1970s, resulting in distinct antigenic characteristics and differences in immunity and cross-protection. Human epidemiological observations and experimental studies have identified lineage-specific differences in adaptive immune responses elicited by contemporary viruses, suggesting that innate immune signaling may contribute to these divergent outcomes. To understand in-depth immunity to contemporary influenza B viruses, we compared viral replication, cytokine production, gene expression, and cellular tropism following infection with representative Victoria- and Yamagata-lineage viruses. We found that, despite broadly similar cytokine profiles in the ferret upper respiratory tract, the two lineages exhibited distinct innate immune kinetics. Yamagata viruses induced rapid early expression of antiviral and inflammatory genes, including SOCS1 and multiple interferon-stimulated genes, whereas Victoria viruses displayed delayed innate immune activation accompanied by greater viral replication. Consistent with the ferret data, Yamagata viruses also induced elevated SOCS1 expression in human PBMCs early after infection. In addition, Yamagata viruses exhibited broader cellular tropism, infecting a wider range of immune cell populations than Victoria viruses. Together, these findings demonstrate that contemporary influenza B virus lineages distinctly engage the host immune system and provide new insight into how lineage-specific innate immune responses may contribute to differences in immunity, cross-protection, and the divergent evolutionary trajectories of Victoria and Yamagata viruses

microbiology↗

bioRxiv2026

A pan-serotype human monoclonal antibody protects against pneumococcal infection by targeting multiple choline binding domain proteins

Streptococcus pneumoniae remains a global health threat, particularly to young children, the elderly, and immunocompromised individuals. Pneumococcal vaccines targeting the bacterial capsule polysaccharide do not protect against all 100+ pneumococcal serotypes, contributing to non-vaccine serotype infections and antibiotic resistance. To address these limitations, we isolated human monoclonal antibodies (mAbs) targeting pneumococcal surface proteins and identified a first-in-class mAb, derived from a patient with prior pneumococcal infection, namely mAb 5995-40. mAb 5995-40 bound multiple pneumococcal proteins, including PcpA and PspA, through a conserved choline-binding domain shared across serotypes. Functionally, mAb 5995-40 provided complete protection in lethal pneumococcal challenge models and improved survival in influenza A, influenza B, and respiratory syncytial virus-associated bacterial coinfection models. Mechanistic studies showed enhanced opsonophagocytic killing, reduced bacterial dissemination, and blocked epithelial translocation. Cryo-electron microscopy identified a repeating motif within the choline-binding domain targeted by mAb 5995-40, highlighting its potential as a broadly protective pneumococcal therapeutic.

immunology↗

bioRxiv2024

Receptor Binding Specificity of a Bovine A(H5N1) Influenza Virus

Outbreaks in the US of highly pathogenic avian influenza virus (H5N1) in dairy cows have been occurring for months creating new possibilities for direct contact between the virus and humans. Eisfeld et al. examined the pathogenicity and transmissibility of a bovine HPAI H5N1 virus isolated from New Mexico in a series of in vitro and in vivo assays. They found the virus has a dual human- and avian virus-like receptor-binding specificity as measured in a solid phase glycan binding assay. Here, we examined the receptor specificity of a bovine HPAI H5N1 virus (A/bovine/OH/B24OSU-432/2024, H5N1, clade 2.3.4.4b) employing four different assays including glycan array technology, bio-layer interferometry (BLI), a solid phase capture assay and hemagglutination of glycan remodeled erythrocytes. As controls, well characterized avian (A/Vietnam/1203/2004, H5N1, clade 1) and human (A/CA/04/2009, H1N1) IAVs were included that bind 2,3- and 2,6-sialosides, respectively. We found that A/bovine/OH/B24OSU-432/2024 preferentially binds to "avian type" receptors (2,3-sialosides). Furthermore, sequence alignments showed that A/bovine has maintained amino acids in its HA associated with 2,3-sialoside (avian) receptor specificity. We conclude that while we find no evidence that A/bovine has acquired human virus receptor binding specificity, ongoing efforts must be placed on monitoring for this trait.

biochemistry↗

bioRxiv2024

Differential Cross-Protective Immunity is Elicited by Infection with Contemporary Influenza B Lineage Viruses

Influenza B virus (FLUBV) significantly contributes to the influenza disease burden and has complicated vaccine development and efficacy, yet remains understudied compared to its counterpart, influenza A virus (FLUAV). Since its isolation in 1940, FLUBV has diverged into two antigenically distinct lineages: Victoria (B/Vic) and Yamagata (B/Yam). Recent human studies and epidemiological modeling reveal differences in immunity elicited by each FLUBV lineage, contributing to higher reinfection rates following B/Yam infection. To investigate disparities in FLUBV lineage cross-protection and immunity, we examined the effects of lineage-specific prior immunity on FLUBV reinfection dynamics. Mice were infected with representative B/Vic and B/Yam viruses from evolutionary distinct clades and subsequently reinfected with heterolineal viruses (i.e., B/Vic [->] B/Yam and B/Yam [->] B/Vic) to assess the extent of protection elicited between the lineages. Using this validated challenge model, we explored potential mechanisms underlying the asymmetric reinfection dynamics observed between the lineages. Our findings align with human observations, indicating that contemporary B/Vic viruses confer cross-protection against contemporary B/Yam infections, whereas contemporary B/Yam viruses do not provide the same degree of protection. Furthermore, we demonstrated that serum antibodies elicited by hemagglutinin vaccination cannot account for the observed heterolineal protection. Rather, antibodies targeting the viral neuraminidase (NA) may play a significant role in eliciting cross-protection to subsequent FLUBV infection. Our findings define asymmetric cross-protection resulting from contemporary FLUBV infection and suggest NA as a potential significant contributor to heterolineal FLUBV protection. This asymmetric immunity may also help explain the proposed extinction of B/Yam viruses since the COVID-19 pandemic. ImportanceInfluenza B viruses (FLUBV) consist of two divergently evolving lineages, Victoria (B/Vic) and Yamagata (B/Yam). Contemporary isolates from these lineages exhibit increased endemic activity and higher evolutionary rates while utilizing distinct mechanisms for evolutionary success. This is exemplified by novel seasonal infection dynamics with Influenza A viruses, differences in cross-protection elicited between the FLUBV lineages, and the potential extinction of B/Yam following the COVID-19 pandemic. We explore FLUBV infection dynamics utilizing contemporary viruses to define the asymmetric immunity elicited between the lineages. Contemporary Yamagata viruses are unable to confer the same breadth of protection as Victoria viruses. This may help explain the higher reinfection rates for Yamagata viruses and suggest a potential contributor to the extinction of this lineage.

microbiology↗