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Malaria-associated lung pathology is a common complication of malaria in adults and often occurs during or even after antimalarial treatment, and current evidence suggests that it is associated with cytokine imbalance and dysregulation of immune responses in the lungs. In this study, we conducted detailed flow cytometry analyses, time-series bulk transcriptomics, and spatial transcriptomics to profile the immune landscape of malaria-associated lung pathology in a mouse malaria model and revealed that IFN-γ signaling in T cells plays a key role in the lung pathology. In addition, we identified a subgroup of CD8-expressing proinflammatory monocytes that exhibit heightened parasite phagocytotic capability.

Trypanosoma vivax is a parasite that causes animal African trypanosomiasis (AAT), a chronic wasting disease that infects economically important livestock animals, which is a particular problem in African countries south of the Sahara. The impact of this disease is significant: it is responsible for over 3 million cattle deaths and an estimated $4.5 billion of annual lost productivity. There is a desperate need to develop new control measures because resistance is now widely reported to the drugs commonly used to treat this infection. We show here that a single dose of an unmodified monoclonal antibody that recognizes IFX—a parasite cell surface protein localized to the flagellum—is sufficient to cure an established T. vivax infection with no parasite reservoirs detectable in peripheral tissues. Our finding validates IFX as a new drug target and provides a rationale route to the development of new drugs to target AAT.

Our study uses Oxford Nanopore direct RNA sequencing of tightly synchronized blood-stage Plasmodium falciparum parasites to investigate the expression of ribosomal RNAs during asexual and sexual development. P. falciparum utilizes distinct types of rRNA during its development. However, due to the challenges of differentiating these highly similar molecules, their regulation and the mechanism underlying the switch between rRNA types remain unclear. We observe significant rRNA degradation in mature gametocytes, leading us to propose that this potentially leads to a reduced number of functional ribosomes when parasites become quiescent and translation is repressed.

Toxoplasma gondii is an obligate parasite whose infection can be detrimental when combined with pregnancy or immunodeficiency. Studies on T. gondii virulence have revealed various secretory proteins that inhibit the host interferon-gamma (IFN-γ) immune response. However, much of the broader virulence landscape remains unclear. To explore the unknown molecular pathways of T. gondii virulence in mice, we searched for immunosuppressive functions in genes encoding non-secretory proteins, associated with fundamental cellular processes of the virulent type I strain. Here, we found that TgJosephin, a highly conserved deubiquitinase, was important for virulence in wild-type mice but not mice lacking the IFN-γ receptor (IFNγR). In addition, TgJosephin expression was dependent on TgRad23, and loss of TgJosephin led to increased ubiquitination of a microtubule protein SPM1. Our results suggest a novel anti-IFN-γ pathway of T. gondii mediated by TgJosephin and SPM1 deubiquitination.

Inflammation is a major driver of tissue perturbation. However, the signals driving these changes on a tissue-intrinsic and molecular level are poorly understood. This study evaluated tissue-specific metabolic perturbations across 11 sampling sites following systemic murine infection with the parasite Toxoplasma gondii . Results revealed relationships between differential metabolite enrichment and variables, including inflammatory signals, pathogen burden, and commensal microbial communities. These data will inform hypotheses about the signals driving specific metabolic adaptation in acute and chronic protozoan infection, with broader implications for infection and inflammation in general.

Chagas disease, caused by the parasite Trypanosoma cruzi, develops into chronic Chagas' cardiomyopathy in ~30% of infected individuals, characterized by conduction disorders, arrhythmias, heart failure, and even sudden cardiac death. Current anti-parasitic treatments are plagued by significant side effects and poor efficacy in the chronic phase of disease; thus, there is a pressing need for new treatment options. A therapeutic vaccine could bolster the protective TH1-mediated immune response, thereby slowing or halting the progression of chronic Chagas' cardiomyopathy. Prior work in mice has demonstrated therapeutic efficacy of a Tc24 recombinant protein vaccine in the acute phase of Chagas disease. However, it is anticipated that humans will be vaccinated therapeutically when in the chronic phase of disease. This study investigates the therapeutic efficacy of a vaccine prototype containing recombinant protein Tc24, formulated with an emulsion containing the Toll-like receptor 4 agonist E6020 as an immunomodulatory adjuvant in a mouse model of chronic T. cruzi infection. Among outbred ICR mice vaccinated during chronic T. cruzi infection, there is a significant increase in the number of animals with undetectable systemic parasitemia (60% of vaccinated mice compared to 0% in the sham vaccine control group), and a two-fold reduction in cardiac fibrosis over the control group. The vaccinated mice produce a robust protective TH1-biased immune response to the vaccine, as demonstrated by a significant increase in antigen-specific IFNγ-production, the number of antigen-specific IFNγ-producing cells, and IgG2a antibody titers. Importantly, therapeutic vaccination significantly reduced cardiac fibrosis in chronically infected mice. This is a first study demonstrating therapeutic efficacy of the prototype Tc24 recombinant protein and E6020 stable emulsion vaccine against cardiac fibrosis in a mouse model of chronic T. cruzi infection.

Background Coinfection has the potential to affect key traits describing the infection dynamics, the severity of the disease and in fine parasite fitness. However, despite its pervasiveness, experimental work investigating how parasites adapt to the conditions provided by a coinfected host is mostly missing. Methods We adopted an experimental evolution approach to investigate if coinfection with the nematode Heligmosomoides polygyrus (Hp) affected the infection dynamics and virulence of the murine malaria parasite Plasmodium yoelii (Py). To this purpose, lines of Py were passaged either in single infected hosts (SI-lines) or in hosts that had been previously infected with Hp (COI-lines). After five and seven passages, the infection dynamics and virulence of evolved lines were compared to the ancestral Py population during single infection trials. COI-lines were also used to infect hosts during coinfection trials, allowing us to compare within-host Py replication when the environment during the evaluation trials matched the environment experienced during the passages and when the two environments were mismatched. Results We found that serial passages increased parasitemia and Py virulence, due to the competitive advantage of genotypes with the fastest replication rate, but SI-lines and COI-lines had relatively similar replication rate and virulence. Hosts infected with evolved lines of Py were also less tolerant (steeper slope between red blood cell counts and parasitemia) but there was no difference between SI-lines and COI-lines. Finally, we found that when COI-lines were used during single infection trials (mismatched environments), they had a slower early replication rate compared to matched-environment trials. Conclusions We did not find strong evidence supporting a divergence between the virulence of SI-lines and COI-lines, possibly due to the cost of virulence paid by COI-lines. However, Py rapidly adapted to the environmental conditions provided by single infected or coinfected hosts, as shown by the slower replication rate found in mismatched-environment trials.

Malaria-associated acute kidney injury (MAKI) is a common complication of Plasmodium infection, affecting ~ 50% of severe malaria cases and associated with increased mortality. However, its immunopathogenesis remains unclear. Interferon-gamma (IFN-gamma) is a crucial cytokine that influences parasite clearance and mediates pathogenesis in experimental models of malaria. This study explored the role of IFN-gamma in kidney pathology in C57BL/6 mice infected with Plasmodium berghei NK65 ( Pb NK65) and P. chabaudi AS ( Pc AS). Pb NK65-infected mice, normally susceptible to severe malaria, were protected from both MAKI and malaria-associated acute respiratory distress syndrome (MA-ARDS) when lacking IFN-gamma. Infected IFN-gamma knockout (KO) mice developed low parasitemia levels, minimal kidney histopathological changes and reduced expression of the kidney injury marker Neutrophil Gelatinase-Associated Lipocalin (NGAL). In contrast, upon Pc AS-infection, IFN-gamma deficiency led to increased parasitemia and aggravated kidney pathology, evidenced by proteinuria, hyaline casts in kidneys and increased renal mRNA expression of Heme Oxygenase 1 (HO - 1) and NGAL. In both models, IFN-gamma induced renal C-X-C Motif Chemokine Ligand 10 (CXCL10) but did not affect Tumor Necrosis Factor-alpha (TNF-alpha) expression. Our data indicate that IFN-gamma exerts a dual effect on kidney pathology, which is conditioned by the mouse model and its impact on parasitemia.

Background: Experimental models using Plasmodium berghei ANKA (PbA)-infected mice have been essential for uncovering cerebral malaria (CM) pathogenesis. However, variability in experimental CM (ECM) incidence, onset, and mortality introduce challenges when analyses rely solely on infection day, which may reflect different disease stages among animals. Methods: We applied machine learning to predict ECM risk and onset in a cohort of 153 C57BL/6, 164 CBA, and 53 Swiss Webster mice. First, we fitted a logistic regression model to estimate the risk of ECM at any day using parasitemia data from day 1 to day 4. Next, we developed and trained a Random Forest Regressor model to predict the exact day of symptom onset. Results: A total of 64.5% of the cohort developed ECM, with onset ranging between 5 and 11 days. Early increases in parasitemia were strong predictors for the development of ECM, with an increase in parasitemia equal to or greater than 0.05 between day 1 and day 3 predicting the development of ECM with 97% sensitivity. The Random Forest model predicted the day of ECM onset with high precision (mean absolute error: 0.43, R2: 0.64). Conclusion: Parasitemia dynamics can effectively identify mice at high risk of ECM, enabling more accurate modeling of early pathological processes and improving the consistency of experimental analyses.

Chagas disease, caused by the protozoan Trypanosoma cruzi, is influenced by both host-related factors and parasite characteristics, including reinfection and strain variability. While the heart is the primary focus of reinfection studies, the effects on the intestinal form of the disease remain poorly understood. In this study, C57BL/6 male mice were infected and subsequently reinfected with the T. cruzi Y strain to assess the immunopathological consequences in the intestinal tract. We analyzed parasitemia levels, systemic cytokines, anti-T. cruzi immunoglobulin levels (IgG, IgG2a, IgG2b), inflammatory infiltrates, neuronal counts, and collagen deposition. Our data showed that reinfection led to reduced parasitemia and did not alter antibody levels generated during primary infection. However, reinfection induced a systemic reduction in IL-4 and IL-10 and an increase in IFN-γ, indicating a shift toward a pro-inflammatory profile. Histopathologically, reinfected mice exhibited intensified intestinal inflammation and increased neuronal destruction in the myenteric plexus, without additional collagen deposition compared to singly infected animals. Although homologous reinfection may enhance parasitemia control through sustained immunoglobulin responses, it exacerbates tissue inflammation and neuronal damage. These findings underscore the dual role of immune responses in controlling parasite burden while potentially contributing to intestinal pathology, highlighting the need for caution when considering reinfection risks in endemic areas.