Biology subjects

Smith, S. C.

Publications and source records attributed to Smith, S. C..

8 recordsLinked to original sources

bioRxiv2026

Vaccine imprinting drives increased SARS-CoV-2 variant infection in children

Virus exposure history, particularly first exposure, is believed to shape vaccine efficacy and infection susceptibility; however, evidence for mechanistic links between immune responses in individuals and epidemiological outcome in populations is scarce. Recent co-circulation of SARS-CoV-2 variants XFG and BA.3.2 has revealed a striking enrichment in BA.3.2 cases among children. By combining epidemiological modeling, serology and monoclonal antibody analysis in children and adults, we show the dependence of effective variant-specific antibodies on vaccination history which may explain birth-year influence on differential susceptibility to these co-circulating variants. Ancestral cross-reactive site I antibodies frequently neutralize BA.3.2, but not XFG. By contrast, Omicron type-specific site I/III and III antibodies frequently neutralize XFG but not BA.3.2, revealing a tradeoff in the ability to neutralize these two co-circulating strains. These findings mechanistically link immune history, variant neutralization, antibody repertoire and variant infection risk, and suggest that vaccination regimens in children should prioritize neutralization breadth.

immunology↗

bioRxiv2025

Vaccine Elicitation of HIV-1 Neutralizing Antibodies Against Both V2 Apex and Fusion Peptide in Rhesus Macaques

Broadly neutralizing antibodies targeting multiple sites of HIV-1 Env vulnerability can be induced by infection, but simultaneous elicitation of neutralizing antibodies (NAbs) against multiple epitopes has not yet been achieved by vaccination. In this study, we designed a dual-epitope vaccine targeting both fusion peptide (FP) and V2 apex and evaluated its capacity to induce NAbs against both epitopes in rhesus macaques. This vaccine combined an FP conjugate with a cocktail of engineered Env trimers with enhanced V2 apex recognition and increased antigen retention in lymph nodes. Immunization of macaques with the dual-epitope vaccine elicited >1000-fold higher autologous tier 2-neutralization titers than the wildtype Env trimer and enhanced heterologous NAb breadth. Both FP and V2-apex monoclonal antibodies (mAb) were isolated from immunized macaques and showed heterologous neutralization with genetic and structural signatures that were similar to well-characterized FP and V2 apex bNAbs, although the V2 apex mAbs showed incomplete maturation. These results demonstrate proof-of-concept for simultaneous vaccine elicitation of NAbs against multiple sites of Env vulnerability, which will likely be critical for an effective HIV-1 vaccine. HIGHLIGHTSO_LIDesigned a dual-epitope vaccine targeting both fusion peptide (FP) and V2 apex C_LIO_LIV2-SET Env trimer conferred higher binding of V2 apex bNAbs, longer retention in draining lymph nodes, and >1000-fold higher induction of autologous neutralization titers compared with wildtype Env trimer C_LIO_LIDual-epitope vaccine enhanced serum tier 2 neutralization breadth C_LIO_LIDual-epitope vaccine elicited FP- and V2 apex-specific neutralizing mAbs with genetic signatures similar to well-characterized FP and V2 apex bNAbs C_LI

immunology↗

bioRxiv2025

Functional, Immunogenetic, and Structural Convergence in Influenza Immunity between Humans and Macaques

Human B cell immunity to the influenza hemagglutinin (HA) stem region, a universal influenza vaccine target, is often stereotyped and immunogenetically restricted, posing challenges for study outside humans. Here, we show that macaques vaccinated with a HA stem immunogen elicit human-like public B cell lineages targeting two major conserved sites of vulnerability, the central stem and anchor epitopes. Central stem antibodies were predominantly derived from VH1-138, the macaque homolog of human VH1-69, a VH-gene preferentially used in human central stem broadly neutralizing antibodies (bnAbs). Similarly, macaques produced anchor bnAbs with the human-like NWP motif. Both bnAb lineages were functionally and structurally analogous to their human counterparts, with recognition mediated largely by germline-encoded motifs. Thus the macaque immunoglobulin repertoire supports human-like public bnAb responses to influenza HA. Moreover, this underscores the utility of homologous germline-encoded immunity, suggesting that immune repertoires of macaques and humans may have been similarly shaped during evolution. HIGHLIGHTS[bullet] Functional human-like public antibody lineages can be elicited to HA stem supersites in macaques. [bullet]Macaque central stem bnAbs are predominantly derived from VH1-138, a VH-gene homologous to human VH1-69. [bullet]The human-like CDR L3 NWP anchor epitope-targeting lineage can be elicited in macaques. [bullet]Central stem and anchor bnAbs from humans and macaques engage their respective epitopes with atomic level similarity.

immunology↗

bioRxiv2023

Mammalian orthoreovirus can exit cells in extracellular vesicles

Several egress pathways have been defined for many viruses. Among these pathways, extracellular vesicles (EVs) have been shown to function as vehicles of non-lytic viral egress. EVs are heterogenous populations of membrane-bound structures released from cells as a form of intercellular communication. EV-mediated viral egress may enable immune evasion and collective viral transport. Strains of nonenveloped mammalian orthoreovirus (reovirus) differ in cell lysis phenotypes, with T3D disrupting cell membranes more efficiently than T1L. However, mechanisms of reovirus egress and the influence of transport strategy on infection are only partially understood. To elucidate reovirus egress mechanisms, we infected murine fibroblasts (L cells) and non-polarized human colon epithelial (Caco-2) cells with T1L or T3D reovirus and enriched cell culture supernatants for large EVs, medium EVs, small EVs, and free reovirus. We found that both reovirus strains exit cells in association with large and medium EVs and as free virus particles, and that EV-enriched fractions are infectious. While reovirus visually associates with large and medium EVs, only medium EVs offer protection from antibody-mediated neutralization. EV-mediated protection from neutralization is virus strain- and cell type-specific, as medium EVs enriched from L cell supernatants protect T1L and T3D, while medium EVs enriched from Caco-2 cell supernatants largely fail to protect T3D and only protect T1L efficiently. Using genetically barcoded reovirus, we provide evidence that large and medium EVs can convey multiple particles to recipient cells. Finally, T1L or T3D infection increases the release of all EV sizes from L cells. Together, these findings suggest that in addition to exiting cells as free particles, reovirus promotes egress from distinct cell types in association with large and medium EVs during lytic or non-lytic infection, a mode of exit that can mediate multiparticle infection and, in some cases, protection from antibody neutralization. AUTHOR SUMMARYThe exit strategy that many viruses use to escape cells is unknown. Reovirus is a nonenveloped human virus and an ideal model system to understand virus exit strategies and their inluence on infection. We found that two different reovirus strains, one that disrupts cell membranes and one that leaves cells largely intact, increase the release of extracellular vesicles (EVs) from cells. Both reovirus strains are released from cells as free particles and in association with EVs, which are membrane-bound structures that function in cell-to-cell communication. Depending on cell type and virus type, EVs can act like an invisibility cloak that shields reovirus from antibodies. EVs can also bundle and ferry reovirus particles between cells. Although we used cells to examine the effects of reovirus association with EVs, it is possible that in mammalian hosts, EVs may shield reovirus from immune defenses and promote more efficient transmission and infection through a strength-in-numbers strategy. Future work building on these findings will test the biological significance of EV-enclosed reovirus and may inform delivery strategies for oncolytic reoviruses to tumor sites. Broadly, these findings enhance our understanding of virus egress strategies and infection principles that may apply to other viruses that travel in EVs.

microbiology↗

bioRxiv2020

Reovirus RNA recombination is sequence directed and generates internally deleted defective genome segments during passage

For viruses with segmented genomes, genetic diversity is generated by genetic drift, reassortment, and recombination. Recombination produces RNA populations distinct from full-length gene segments and can influence viral population dynamics, persistence, and host immune responses. Viruses in the Reoviridae family, including rotavirus and mammalian orthoreovirus (reovirus), have been reported to package segments containing rearrangements or internal deletions. Rotaviruses with RNA segments containing rearrangements have been isolated from immunocompromised and immunocompetent children and in vitro following serial passage at high multiplicity. Reoviruses that package small, defective RNA segments have established chronic infections in cells and in mice. However, the mechanism and extent of Reoviridae RNA recombination are undefined. Towards filling this gap in knowledge, we determined the titers and RNA segment profiles for reovirus and rotavirus following serial passage in cultured cells. The viruses exhibited occasional titer reductions characteristic of interference. Reovirus strains frequently accumulated segments that retained 5' and 3' terminal sequences and featured large internal deletions, while similar segments were rarely detected in rotavirus populations. Using next-generation RNA-sequencing to analyze RNA molecules packaged in purified reovirus particles, we identified distinct recombination sites within individual viral gene segments. Recombination junction sites were frequently associated with short regions of identical sequence. Taken together, these findings suggest that reovirus accumulates defective gene segments featuring internal deletions during passage and undergoes sequence-directed recombination at distinct sites. IMPORTANCEViruses in the Reoviridae family include important pathogens of humans and other animals and have segmented RNA genomes. Recombination in RNA virus populations can facilitate novel host exploration and increased disease severity. The extent, patterns, and mechanisms of Reoviridae recombination and the functions and effects of recombined RNA products are poorly understood. Here, we provide evidence that mammalian orthoreovirus regularly synthesizes RNA recombination products that retain terminal sequences but contain internal deletions, while rotavirus rarely synthesizes such products. Recombination occurs more frequently at specific sites in the mammalian orthoreovirus genome, and short regions of identical sequence are often detected at junction sites. These findings suggest that mammalian orthoreovirus recombination events are directed in part by RNA sequences. An improved understanding of recombined viral RNA synthesis may enhance our capacity to engineer improved vaccines and virotherapies in the future.

microbiology↗

bioRxiv2018

Host-pathogen coevolution increases genetic variation in susceptibility to infection

It is common to find considerable genetic variation in susceptibility to infection in natural populations. We have investigated whether natural selection increases this variation by testing whether host populations show more genetic variation in susceptibility to pathogens that they naturally encounter than novel pathogens. In a large cross-infection experiment involving four species of Drosophila and four host-specific viruses, we always found greater genetic variation in susceptibility to viruses that had coevolved with their host. We went on to examine the genetic architecture of resistance in one host species, finding that there are more major-effect genetic variants in coevolved host-parasite interactions. We conclude that selection by pathogens increases genetic variation in host susceptibility, and much of this effect is caused by the occurrence of major-effect resistance polymorphisms within populations.

evolutionary biology↗

bioRxiv2017

Host shifts result in parallel genetic changes when viruses adapt to closely related species

Host shifts, where a pathogen invades and establishes in a new host species, are a major source of emerging infectious diseases. They frequently occur between related host species and often rely on the pathogen evolving adaptations that increase their fitness in the novel host species. To investigate genetic changes in novel hosts, we experimentally evolved replicate lineages of an RNA virus (Drosophila C Virus) in 19 different species of Drosophilidae and deep sequenced the viral genomes. We found a strong pattern of parallel evolution, where viral lineages from the same host were genetically more similar to each other than to lineages from other host species. When we compared viruses that had evolved in different host species, we found that parallel genetic changes were more likely to occur if the two host species were closely related. This suggests that when a virus adapts to one host it might also become better adapted to closely related host species. This may explain in part why host shifts tend to occur between related species, and may mean that when a new pathogen appears in a given species, closely related species may become vulnerable to the new disease.

evolutionary biology↗

bioRxiv2016

Vertically transmitted rhabdoviruses are found across three insect families and have dynamic interactions with their hosts

A small number of free-living viruses have been found to be obligately vertically transmitted, but it remains uncertain how widespread vertically transmitted viruses are and how quickly they can spread through host populations. Recent metagenomic studies have found several insects to be infected with sigma viruses (Rhabdoviridae). Here, we report that sigma viruses that infect Mediterranean fruit flies (Ceratitis capitata), Drosophila immigrans, and speckled wood butterflies (Pararge aegeria) are all vertically transmitted. We find patterns of vertical transmission that are consistent with those seen in Drosophila sigma viruses, with high rates of maternal transmission, and lower rates of paternal transmission. This mode of transmission allows them to spread rapidly in populations, and using viral sequence data we found the viruses in D. immigrans and C. capitata had both recently swept through host populations. The viruses were common in nature, with mean prevalences of 12% in C. capitata, 38% in D. immigrans and 74% in P. aegeria. We conclude that vertically transmitted rhabdoviruses may be widespread in insects, and that these viruses can have dynamic interactions with their hosts.

evolutionary biology↗