Biology subjects

Harris, S. J.

Publications and source records attributed to Harris, S. J..

5 recordsLinked to original sources

bioRxiv2025

CCR6 is essential for effective immunity against Mycobacterium tuberculosis infection in mice

Tuberculosis (TB) is a global epidemic that has threatened human health throughout recorded history. TB disease, caused by infection with Mycobacterium tuberculosis (M.tb), is heterogeneous between individuals, and clinical TB outcomes are impacted by genetic and environmental risk factors. Infected individuals must maintain a careful balance of cytokines and chemokines following M.tb infection to eliminate or contain the bacteria without causing excessive inflammation and lung damage. The CC chemokine receptor 6 (CCR6) is expressed by several immune cell populations that are classically involved in the pathogenesis of M.tb infection. However, the precise functions of CCR6 in the context of TB disease remain underexplored. Here, we show that mice lacking the CCR6 receptor (CCR6 KO) fail to restrict bacterial burden in the lungs, leading to increased disseminated infection at 4-weeks post-infection compared to wild-type C57BL/6J (B6) mice, with a more pronounced effect in females. CCR6 KO mice also developed necrotic pulmonary lesions, phenotypically distinct from B6 mice, and produced elevated levels of pro-inflammatory cytokines and chemokines at the onset of adaptive immunity, particularly IL-17. Long-term infection experiments revealed that the absence of CCR6 enhances risk for mortality following M.tb infection, particularly in females. This study provides insights into the role of CCR6 during TB pathogenesis and establishes its importance in maintaining protective immunity against M.tb within the context of a genetically tractable mouse model that forms necrotic pulmonary granulomas.

microbiology↗

bioRxiv2025

Cathepsin Z is a conserved susceptibility factor underlying tuberculosis severity

Tuberculosis (TB) outcomes vary widely, from asymptomatic infection to mortality, yet most animal models do not recapitulate human phenotypic and genotypic variation. The genetically diverse Collaborative Cross mouse panel models distinct facets of TB disease that occur in humans and allows identification of genomic loci underlying clinical outcomes. We previously mapped a TB susceptibility locus on mouse chromosome 2. Here, we identify cathepsin Z (Ctsz) as a lead candidate underlying this TB susceptibility and show that Ctsz ablation leads to increased bacterial burden, CXCL1 overproduction, and decreased survival in mice. Ctsz disturbance within murine macrophages enhances production of CXCL1, a known biomarker of TB severity. From a Ugandan household contact study, we identify significant associations between CTSZ variants and TB disease severity. Finally, we examine patient-derived TB granulomas and report CTSZ localization within granuloma-associated macrophages, placing human CTSZ at the host-pathogen interface. These findings implicate a conserved CTSZ-CXCL1 axis in humans and genetically diverse mice that mediates TB disease severity.

genetics↗

bioRxiv2023

Cross population comparison of complex migration strategies in a declining oceanic seabird

Human-driven change is impacting ecosystems globally, with consequential declines in biodiversity. Long-distance migrants are particularly susceptible as they depend on conditions over large geographical scales and are more likely to experience a greater range of pressures. One long-distance migrant that has experienced substantial declines across the North-East Atlantic is the Arctic Skua Stercorarius parasiticus however, little is known about their migratory behaviour or the routes they undertake. We used geolocators with salt-water switches to track Arctic Skuas from four breeding populations. To investigate migration strategies, we developed a Hidden Markov Model approach that used saltwater immersion data to classify stopovers and transit flights. We found that the skuas used several discrete staging areas during their south and northbound migrations with an area of apparent high marine productivity in the mid-North Atlantic being of high importance. Extensive overlap of individuals from different breeding populations occurred in staging areas, resulting in weak spatial connectivity between breeding and staging areas, further emphasizing their importance. At the population-level, variation in migration strategies was driven by individuals from Svalbard, which is declining less than the other populations tracked. Relative location of wintering areas also influenced migration strategies, with individuals migrating further spending a smaller proportion of their migration at stopovers compared to those wintering closer, and instead employed a fly-and-forage strategy. Identifying the complex non-breeding distribution, weak migratory connectivity and highly conserved migration strategies of Arctic Skuas is a vital step to link how conditions experienced during migration influences population dynamics and to prioritise future research and conservation actions.

ecology↗

bioRxiv2023

Ocean-scale variation in migration schedules of a long-distance migratory seabird is fully compensated upon return to the breeding site

BackgroundMigratory birds generally have tightly scheduled annual cycles, in which delays can have carry-over effects on the timing of later events, ultimately impacting reproductive output. Whether temporal carry-over effects are more pronounced among migrations over larger distances, with tighter schedules, is a largely unexplored question. MethodsWe tracked individual Arctic Skuas Stercorarius parasiticus, a long-distance migratory seabird, from eight breeding populations between Greenland and Siberia using light-level geolocators. We tested whether migration schedules among breeding populations differ as a function of their use of seven widely divergent wintering areas across the Atlantic Ocean, Mediterranean Sea and Indian Ocean. ResultsBreeding at higher latitudes led not only to later reproduction and migration, but also faster spring migration and shorter time between return to the breeding area and clutch initiation. Wintering area was consistent within individuals among years; and more distant areas were associated with more time spent on migration and less time in the wintering areas. Skuas adjusted the period spent in the wintering area, regardless of migration distance, which buffered the variation in timing of autumn migration. Choice of wintering area had only minor effects on timing of return at the breeding area and timing of breeding and these effects were not consistent between breeding populations. ConclusionThe lack of a consistent effect of wintering area on timing of return between breeding areas indicates that individuals synchronize their arrival with others in their population despite extensive individual differences in migration strategies.

ecology↗

bioRxiv2021

Binding stoichiometry and structural model of the HIV-1 Rev/Importin beta complex

HIV-1 Rev mediates the nuclear export of intron-containing viral RNA transcripts and is essential for viral replication. Rev is imported into the nucleus by the host protein Importin {beta} (Imp{beta}), but how Rev associates with Imp{beta} is poorly understood. Here we report biochemical, biophysical and structural studies of the Imp{beta}/Rev complex. Gel shift, native mass spectrometry and isothermal titration calorimetry data reveal that Imp{beta} binds two Rev monomers through independent binding sites. Small-angle X-ray scattering (SAXS) data suggest that the HEAT repeats of Imp{beta} retain an extended conformation upon binding Rev, which according to NMR data is primarily recognized through its helical hairpin domain. Peptide scanning data and charge-reversal mutations identify the N-terminal tip of Rev helix 2 within Revs Arginine-Rich Motif (ARM) as a primary Imp{beta} binding epitope. Crosslinking mass spectrometry and compensatory mutagenesis data combined with molecular docking simulations suggest a structural model in which one Rev monomer binds to the C-terminal half of Imp{beta} with Rev helix 2 roughly parallel to the HEAT-repeat superhelical axis while the other monomer binds to the N-terminal half. These findings shed light on the molecular basis of Rev recognition by Imp{beta} and highlight an atypical binding behaviour that distinguishes Rev from canonical cellular Imp{beta} cargos.

biochemistry↗