Title: Malarial infections in the context of invasive non-typhoidal Salmonella
Description: Apicomplexan parasites of the genus Plasmodium have been infecting humans for millions of years, leaving their mark on the human genome and probably playing a role in shaping the distribution of global wealth. The disease they cause, malaria, continues to claim the lives of more than half a million people every year, mostly young children in Sub-Saharan Africa. Including deaths, immediate symptoms, and lasting complications of severe malaria syndromes, the disease causes an estimated annual loss of over 80 million life years due to ill health, disability, or early mortality. Populations in regions where malaria is endemic are also exposed to a number of other pathogenic organisms; co-infections occur between Plasmodium species and a wide variety of viruses, other eukaryotic parasites, and bacteria. Invasive bacterial species are a widespread threat in Sub-Saharan Africa, where up to 12% of people admitted to hospital with fever are reported to have culturable bacteria in their bloodstream.

For decades, evidence has suggested that malaria may contribute to the prevalence of invasive bacterial disease in Sub-Saharan Africa; human and mouse studies have shown that indeed plasmodial infection increases susceptibility to invasive bacterial infection and mortality, in particular due to invasive non-typhoidal Salmonella (NTS). Invasive NTS are of especial interest as they are consistently among the most commonly identified bacteria isolated from blood culture. NTS rarely causes invasive disease in the developed world, remaining as an enteric infection and eliciting unpleasant but usually self-limiting symptoms. In contrast, multiple environmental and bacteria-intrinsic factors in Sub-Saharan Africa contribute to a greater propensity of NTS to breach the gut wall and spread systemically. Malaria, as mentioned, is well established as one such factor. However, other contributing determinants of invasion mean that a substantial number of Plasmodium infections may be contracted by people already harboring systemic NTS infection and may therefore exhibit altered parasite development or progression of malarial disease.

The impact of existing invasive NTS infection on Plasmodium has not been elucidated. In this thesis we present our findings, using a mouse model of co-infection, that invasive NTS inhibits liver-stage Plasmodium berghei development. We demonstrate that this inhibition is at least in part through induction of a host response that is detrimental to the parasite and does not require live NTS infection. Invasive NTS-induced suppression of liver-stage growth was independent of Type I IFN, IFN-γ and TNF-α signaling, although all three of these factors are upregulated in NTS-infected mice in our model. Plasmodial disease is a consequence of asexual blood-stage parasite replication. Using our model of co-infection we show that progression to this stage of disease is hampered, not only through reduction of liver parasite burden, but also through direct suppression of blood-stage parasite population growth. Although we found that killed NTS do not suppress blood-stage P. berghei populations, mice treated with heat-killed NTS survived longer, indicating that killed bacteria may be sufficient to prevent development of experimental cerebral malaria.