Thermoneutrality and severe malaria: investigating the effect of warmer environmental temperatures on the inflammatory response and disease progression

ABSTRACT: Most studies using murine disease models are conducted at a housing temperature of 20ºC that is sub-optimal (ST) for mice, eliciting changes in metabolism and response to disease. Experiments performed at a thermoneutral temperature (TT) of 37ºC have revealed an altered immune response to pathogens and experimental treatments in disease models (e.g. cancer, obesity, Alzheimer’s disease). These alterations in metabolic activity have implications for the use of murine models to understand human diseases and their translation to clinical research. How such conditions affect the inflammatory response to infection with Plasmodium berghei ANKA (PbA) and subsequent disease progression is unknown. We hypothesized that changes in environmental temperature modulate immune cells and modify host response to malaria disease. To test this hypothesis, we conducted two sets of experiments to determine: (1) the inflammatory response of bone-marrow derived macrophages (BMDM) to infectious agents at different environmental temperatures and (2a) the inflammatory response to malarial agents injection in a peritonitis model and (2b) disease progression in PbA-infected mice at TT compared to ST. Firstly, BMDMs were incubated and stimulated with LPS at a fever-like temperature (FT; 39ºC), TT (37ºC) or low-temperatures (LT; 30ºC) mimicking ST for 6, 12 and 24 hours. We observed an that BMDMs released increased inflammation markers (i.e. nitric oxide and pro-inflammatory cytokine at FT and TT compared to LT, with an increase overtime. Secondly, C57BL6 mice were acclimatized for 3 weeks at TT (28 – 31ºC) or ST (20 – 22ºC). In one study, mice were injected intraperitoneally with nHZ or Leishmania at both temperatures, and immune cells were counted and subtyped from the peritoneal cavity (PEC) fluid. Cytokine concentrations and extracellular vesicle (EV) profiles were also determined from the PEC. Apart from Leishmania injection resulting in decreased cell recruitment and a higher phagocytosis of nHZ in mice housed at TT, we did not observe many temperature-based differences. We found 398 upregulated and 293 downregulated pro-inflammatory genes in mice injected with nHZ, that were similar to those previously elicite with Leishmania injections, at both temperatures. EV profile did not differ significantly at TT compared to ST but we report the presence of proteosome-derived and platelet-derived EVs in a murine parasitic murine model at both temperatures. In another study, mice were injected with luciferase-tagged PbA-infected RBCs and monitored until death. We observed metabolic changes (i.e. lower body weight and temperature loss) in mice housed at TT but these did not result to noticeable changes in survivability, parasite organ sequestration or serum cytokine levels compared to ST. To our knowledge, these experiments are the first to investigate the effect of thermoneutrality on a malaria murine model. Despite results suggesting that thermoneutrality does not significantly alter severe malarial disease progression or host inflammatory response to parasitic agents, we found important metabolic difference in mice housed at TT. Our results offer insights on how thermoneutrality might impact a severe malaria murine model and directions for more targeted investigations. This constitutes a first step in elucidating factors that may explain the lack of translatability to clinical trial.

ORGANISM(S): Mus musculus

PROVIDER: GSE221454 | GEO | 2023/05/24

REPOSITORIES: GEO