The microbiome and the gut-lung axis in tuberculosis: interplay in the course of disease and treatment

Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis (MTB) that remains a significant global health challenge. The extensive use of antibiotics in tuberculosis treatment, disrupts the delicate balance of the microbiota in various organs, including the gastrointestinal and respiratory systems. This gut-lung axis involves dynamic interactions among immune cells, microbiota, and signaling molecules from both organs. The alterations of the microbiome resulting from anti-TB treatment can significantly influence the course of tuberculosis, impacting aspects such as complete healing, reinfection, and relapse. This review aims to provide a comprehensive understanding of the gut-lung axis in the context of tuberculosis, with a specific focus on the impact of anti-TB treatment on the microbiome

The impact of innate immunity on malaria parasite infection dynamics in rodent models

Decades of research have probed the molecular and cellular mechanisms that control the immune response to malaria. Yet many studies offer conflicting results on the functional impact of innate immunity for controlling parasite replication early in infection. We conduct a meta-analysis to seek consensus on the effect of innate immunity on parasite replication, examining three different species of rodent malaria parasite. Screening published studies that span four decades of research we collate, curate, and statistically analyze infection dynamics in immune-deficient or -augmented mice to identify and quantify general trends and reveal sources of disagreement among studies. Additionally, we estimate whether host factors or experimental methodology shape the impact of immune perturbations on parasite burden. First, we detected meta-analytic mean effect sizes (absolute Cohen’s h) for the difference in parasite burden between treatment and control groups ranging from 0.1475 to 0.2321 across parasite species. This range is considered a small effect size and translates to a modest change in parasitaemia of roughly 7-12% on average at the peak of infection. Second, we reveal that variation across studies using P. chabaudi or P. yoelii is best explained by stochasticity (due to small sample sizes) rather than by host factors or experimental design. Third, we find that for P. berghei the impact of immune perturbation is increased when young or female mice are used and is greatest when effector molecules (as opposed to upstream signalling molecules) are disrupted (up to an 18% difference in peak parasitaemia). Finally, we find little evidence of publication bias suggesting that our results are robust. The small effect sizes we observe, across three parasite species, following experimental perturbations of the innate immune system may be explained by redundancy in a complex biological system or by incomplete (or inappropriate) data reporting for meta-analysis. Alternatively, our findings might indicate a need to re-evaluate the efficiency with which innate immunity controls parasite replication early in infection. Testing these hypotheses is necessary to translate understanding from model systems to human malaria

The evolutionary ecology of parasite strategies for within-host survival

Plasmodium parasites, the causal agents of malaria, engage in complex interactions with their hosts, however despite decades of research much of their life cycle remains unexplored. A deeper understanding of the strategies parasite have evolved to survive within, and exploit hosts, offers novel approaches for treating infections. By integrating tools from different fields within parasitology with an eco-evolutionary framework, I explore some of the strategies Plasmodium chabaudi parasites deploy within poorly studied aspects of their life cycle. Using this rodent malaria model, I first tested the relationship between host daily rhythms and the transition of parasites from developing in the liver to replication in the blood. In contrast to expectation, host circadian rhythms(i.e. feeding-fasting rhythms) do not influence the timing or the manner by which parasites begin the blood stage of their lifecycle. Moreover, how parasites undertake this critical step appears selectively neutral, suggesting that the rhythmicity in blood stage replication that is well-known in malaria parasites is rapidly established once in the blood. I then explored the ecology of sequestration (withdrawal from the blood to organs), a parasite strategy assumed to facilitate immune evasion and that is related to the manifestation of severe disease phenotypes, and potentially transmission. Specifically, I tested whether sequestration is scheduled to align with host rhythms driven by feeding-fasting or by photoperiod. I found little evidence for host rhythms affecting sequestration, or its consequences for replication. However, whether or not hosts experience disruption to their own rhythms influences sequestration in the lungs. Finally, I resolved controversy and conflicting reports concerning the role of innate immune responses on infection dynamics, especially during the establishment of infections. My comprehensive meta-analysis show that innate immune factors have only a minor impact on parasite replication in the blood. Overall, my thesis contributes to malaria knowledge by uncovering new aspects of parasite ecology and interactions with the host