Tick-borne coinfections modulate CD8+ T cell response and progressive leishmaniosis

Leishmania infantumcauses human Visceral Leishmaniasis and Leishmaniosis (CanL) in reservoir host, dogs. As infection progresses to disease in both humans and dogs there is a shift from controlling, Type 1, immunity to a regulatory, exhausted, T cell phenotype. In endemic areas, association between tickborne coinfections (TBC) andLeishmaniadiagnosis and/or clinical severity has been demonstrated. To identify immune factors correlating with disease progression, we prospectively evaluated a cohort ofL. infantuminfected dogs from 2019-2022. The cohort was TBC-negative with asymptomatic leishmaniosis at the time of enrollment. We measured TBC serology, anti-Leishmaniaantigen T cell immunity, CanL serological response, parasitemia, and disease severity to probe how nascent TBC perturbs the immune state. At the conclusion, TBC+ dogs with CanL experienced greater increases in anti-Leishmaniaantibody reactivity and parasite burden compared to dogs that did not have incident TBC during the study. TBC+ dogs were twice as likely to experience moderate (LeishVet stage 2) or severe/terminal disease (LeishVet stage 3/4). Prolonged exposure to TBC was associated with a shift inLeishmaniaantigen-induced IFNγ/IL-10 and enhanced CD8 T cell proliferation. Frequency of proliferating CD8 T cells significantly correlated with parasitemia and antibody reactivity. TBC exacerbated parasite burden and immune exhaustion. These findings highlight the need for combined vector control efforts as prevention programs for dogs inLeishmaniaendemic areas to reduce transmission to humans. Public health education efforts should aim to increase awareness of the connection between TBC and leishmaniosis.