Biology subjects

Sheneman, K. R.

Publications and source records attributed to Sheneman, K. R..

3 recordsLinked to original sources

bioRxiv2026

Disruption of a CCR5-like immunoglobulin gene is linked to plague susceptibility in black-footed ferrets

Black-footed ferrets (Mustela nigripes) are among the worlds most endangered mammals and remain highly vulnerable to sylvatic plague caused by Yersinia pestis, yet the genetic basis of this susceptibility has remained unknown. Current conservation strategies rely on vaccination of captive-bred animals and large-scale flea control with insecticides, approaches that are costly, labor-intensive, and difficult to implement across the species natural range. Several closely related mustelid species, including the domestic ferret, are substantially more resistant to plague, providing an opportunity to identify naturally evolved immune mechanisms through comparative immunogenomics. Here we identify a conserved class of immunoglobulin lambda variable genes encoding unusually long antigen-binding loops with CCR5-mimicking sequence features that are widespread among Caniformia species. Because CCR5 has been implicated in host interactions with Yersinia species, we hypothesized that antibodies encoded by these germline genes contribute to plague resistance through receptor-like molecular mimicry. Consistent with this hypothesis, we show that these genes are under strong purifying selection in mustelids, are actively expressed in antibody repertoires, and monoclonal antibodies encoded by them reduced intracellular Y. pestis survival in macrophages. In contrast, all analyzed black-footed ferrets carried a frameshifting deletion resulting in loss of gene expression. These findings identify a naturally disrupted germline antibody gene as a candidate determinant of plague susceptibility in black-footed ferrets, demonstrating that variation in germline immunoglobulin genes can influence susceptibility to a lethal infectious disease. Ultimately, these findings lay the groundwork for genetically informed conservation management and the development of new antibody-based anti-plague strategies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/734856v2_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@19d8ac1org.highwire.dtl.DTLVardef@a37aorg.highwire.dtl.DTLVardef@1ecd1e0org.highwire.dtl.DTLVardef@c6fd67_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

Yersinia pestis actively inhibits the production of extracellular vesicles by human neutrophils

Yersinia pestis is the etiologic agent of the plague. A hallmark of plague is subversion of the host immune response by disrupting host signaling pathways required for inflammation. This non-inflammatory environment permits bacterial colonization and has been shown to be essential for disease manifestation. Previous work has shown that Y. pestis inhibits phagocytosis and degranulation by neutrophils. Manipulation of these key vesicular trafficking pathways suggests that Y. pestis influences EV secretion, cargo selection, trafficking, and/or maturation. Our goal was to define the EV population produced by neutrophils in response to Y. pestis and determine how these vesicles might influence inflammation. Toward these goals, EVs were isolated from human neutrophils infected with Y. pestis or a mutant lacking bacterial effector proteins known to manipulate host cell signaling. Mass spectrometry data revealed that cargoes packaged in EVs isolated from mutant infected cells were enriched with antimicrobials and cytotoxic proteins, contents which differed from uninfected and Y. pestis infected cells. Further, EVs produced in response to Y. pestis lacked inflammatory properties observed in those isolated from neutrophils responding to the mutant. Together, these data demonstrate that Y. pestis actively inhibits the production of antimicrobial EVs produced by neutrophils, likely contributing to immune evasion.

microbiology↗

bioRxiv2023

Inhibition of type III secretion system induced leukotriene B4 production by Yersinia pestis: A mechanism for early immune evasion

Subverting the host immune response to inhibit inflammation is a key virulence factor of Yersinia pestis. The inflammatory cascade is tightly controlled via the sequential action of lipid and protein mediators of inflammation. Because delayed inflammation is essential for Y. pestis to cause lethal infection, defining the mechanisms used by Y. pestis to manipulate the inflammatory cascade is necessary to understand this pathogens virulence. While previous studies have established that Y. pestis actively inhibits the expression of host proteins that mediate inflammation, there is currently a gap in our understanding of inflammatory lipid mediator response during plague. Here we use in vivo lipidomics to define the synthesis of lipid mediators of inflammation within the lungs during pneumonic plague. Interestingly, while we observed an early cyclooxygenase response during pneumonic plague, there was a significant delay in the synthesis of leukotriene B4 (LTB4), a pro-inflammatory lipid chemoattractant and activator of immune cells. Furthermore, in vitro studies with primary leukocytes from mice and humans further revealed that Y. pestis actively inhibited the synthesis of LTB4. Finally, using Y. pestis mutants in the Ysc type 3 secretion system (T3SS) and Yersinia outer protein (Yop) effectors, we demonstrate that leukocytes recognize the T3SS to initiate the synthesis of LTB4 rapidly. However, the Yop effectors secreted through the same system effectively inhibit this host response. Together, these data demonstrate that Y. pestis actively inhibits the synthesis of LTB4, an inflammatory lipid, required for rapid recruitment of leukocytes to the site of infection. Author SummaryYersinia pestis, the bacteria that causes plague, targets the hosts innate immune response to inhibit inflammation. Because the generation of this non-inflammatory environment is required for infection, we are interested in mechanisms used by Y. pestis to block inflammation. Lipid mediators are potent signaling molecules that regulate multiple host immune responses, including inflammation. While there have been studies on how Y. pestis blocks the proteins that mediate inflammation, there is a gap in our understanding of the inflammatory lipid mediator response during plague. Here we show that Y. pestis inhibits the production of one of these critical lipid mediators, leukotriene B4, by host immune cells. Furthermore, we identify both the signals that induce LTB4 production by leukocytes and the mechanisms used by Y. pestis to inhibit this process. Together, these data represent the first comprehensive analysis of inflammatory lipids produced during plague and improve our current understanding of how Y. pestis manipulates the host immune response to generate a permissive non-inflammatory environment required for bacterial colonization.

microbiology↗