Investigating the impact of malaria and tuberculosis co-infections on disease outcomes

Background

The combined global burden of tuberculosis (TB) and malaria results in over 2 million deaths every year, and is associated with over 100 million disability-adjusted life-years (DALYs). Both of these devastating diseases disproportionatly affect the global south and the majority of cases occur within overlapping endemic regions. Is therefore no surprise that co-infections with these two pathogens are extremely widespread. However, the resulting outcome of this co-infection is complex, and is further impacted by the fact that the majority of severe complications of both diseases occur in children and adolescents. Therefore, understanding the unique individual characteristics which impact patient outcome is important to elucidate. 

The ability of Plasmodium parasites, the causative agents of malaria, to induce immunosupporession is well documented, and there is evidence that it may contribute to the reactivation of dormant TB infections. Experimental animal infections have demonstrated that malaria co-infection exacerbates TB infections both in vitro and in vivo, but the underling mechanisms remain undetermined. Moreover, there is evidence from co-infections with other bacterial pathogens such as Salmonella that malaria infection can increase epithelial barrier permeability, leading to an increase in bacterial invasion and dissemination. It is currently unknown whether there are similar impacts on the establishment of extrapulmonary TB infections, but as a large percentage of malaria infections result in pulmonary symptoms, including respiratory distress and epithelial damage, we hypothesize that co-infection will similarly increase TB dissemination and egress from the lung alveoli into interstitial tissues, facilitating severe infection. 

We predicted that ongoing or previous malaria infections may impact the severity of TB infections and the likelihood of reactivation of latent infections, necessitating more stringent treatement regimens. This is potentially problematic, as the gold standard course of antibiotics against TB is an extenstive 6 month course of treatment with drugs that have known side effects including potential damage to the liver, the initial site of malaria infections. By increasing our understanding of the interplay between TB and malaria in co-infection models and analyzing clinical samples from an adolescent cohort from a region endemic to both diseases to identify new biomarkers of co-infection, we can inform clinical treatments to ensure that patients are treated with a precision medicine approach to provide a balance between aggressive treatment to ensure bacterial clearance and side effect management. 

Aims

Perform a trascriptomic analysis of whole blood from Gambian adolescents with coinfection.

The Mooney lab has previously collected and archived whole blood samples from a cohort of 259 adolesents from a highly endemic region, The Gambia. These samples been screened for the prevelance of malaria infection within the cohort, and based on local incidence rates and preliminary screening we predicted that 10-12% of these samples will be seropositive for TB exposure. The student will perform transcriptomic (RNAseq) analysis on a subset of these samples and perfrom computationa anlysis to cross-reference this data against patient demographics and immune cytokine profiling to determine the impact of disease on biomarkers of infection using generalized linear models.

Establish co-culture microtissue models of TB and malaria co-infection to determine the impact of malaria-induced immunosuppression on infection control and bacterial dissemination.

The Moule lab uses three-dimensional microtissues models of the human lung to evaluate bacterial host-pathogen interactions in a multicellular environment consisting of epithelial cells, endothelial cells, and myeloid immune cells. The three dimensional nature of these models allows examination of dissemination across an epithelial barrier as well as the cross-talk between host cells. In this project, our existing models will be expanded to allow plasmodium culture on the endothial/bloodstream chamber of the model, and BCG infections will be performed at the air-liquid interface to model TB infection and follow the progress of infection over time. 

Investigate the effects of malaria infection on lung permeability and bacterial dissemination using a mouse model of co-infection

Using the Plasmodium chabaudi mouse model established in the Mooney lab, we will perform co-infection studies using BCG to examine the impact on lung permeability, TB reactivation, and establishment of extrapulmonary TB infections to determine the impact of malaria-associated immune suppression on bacterial infection severity and outcome.

Training Outcomes

Over the course of this project, the student will become familiar with general parasitological, bacteriological and immunological techniques and learn to perform in vivo and in vitro infections with both pathogens. In addition, they will undertake extensie training in genomics, bioinformatics and statistical analysis using generalized linear models. This will include using computation analysis and writing bespoke code to compare datasets and identify biomarkers of co-infection, resulting in an understanding of how precision medicine strategies can be applied to improve treatment outcomes and reduce unwanted side effects.