A study of the immune response to malaria using systems-level analysis strategies

Pathogens causing febrile infections can engage with our immune system on several levels, leading to a broad range of disease spectra. Malaria, caused by infections with Plasmodium falciparum continues to impose a global burden, despite being one of the oldest febrile diseases plaguing humans. In malaria, the parasite-blood stage is linked to symptomatic disease due to the parasite invading erythrocytes, sequestration, and triggering inflammation and a systemic immune response. This thesis investigated the peripheral immune response to P. falciparum malaria and other febrile infections using systems-level approaches to understand the activation and interaction of different immune compartments in the host response. These approaches are beneficial in infection immunology as they offer a comprehensive view of interactions and networks of the immune system, providing insights into mechanisms affecting disease outcomes and generating new hypotheses.

In Study I, we characterized the immune response of patients treated for acute malaria in Sweden after returning from travel. Using a systems-level approach, we first described the immune landscape during and after acute malaria and explored the impact of previous exposure. We revealed that previous malaria exposure was associated with a reduced expansion of yo T cells. We also showed that this reduction was strongly associated with reduced inflammatory cytokines and further associated with an increased breadth and levels of cytophilic antibodies and expansion of FcyRIII+ monocytes.

In Study II, we investigated how clinical malaria perturbs the blood plasma proteome, the origins of these perturbations, and the potential functions of the circulating proteins, as well as how proteomic profiles can stratify patients into subgroups associated with disease severity. Using an unbiased, data-driven approach we revealed molecular patterns linked to disease severity, immune cell regulation, and tissue-specific origins. The proteomic profile-based patient stratification linked to disease severity offered novel insights into the systemic host response to malaria.

In Study III, we followed up on findings from Study I by focusing on the impact of previous malaria exposure on monocytes during acute malaria. We discovered transcriptional changes in monocytes linked to the acute inflammatory response and immune-modulatory mechanisms affecting the B cell response during malaria.

In Study IV, we utilized computational approaches to assess how plasma protein profiles were associated with the magnitude and longevity of the antibody response after acute malaria. We identified elevated levels of pro-inflammatory mediators associated with low antibody responses, suggesting that excessive inflammation may hinder effective B cell activation and long-lasting immunity. Conversely, high levels of soluble FcRL5 and other FcRL-family proteins were linked to robust and sustained antibody responses, indicating their potential as markers for effective B cell activation.

In Study V, we investigated how a selection of host response proteins in plasma can be used to distinguish different pathogens causing febrile diseases in patients who had traveled to tropical regions. Our findings revealed that malaria exhibited the most distinct protein profiles in this comparison, corroborating other malaria- specific studies that highlight the significant role of certain disease-specific markers.

Collectively, the studies in this thesis provide an increased understanding of the immune response to malaria and elucidate how various components of our defense system are coordinated to combat the infection, leading to improved disease outcomes.

List of scientific papers

I. Systems analysis shows a role of cytophilic antibodies in shaping innate tolerance to malaria Lautenbach MJ, Yman V, Silva CS, Kadri N, Broumou I, Chan S, Angenendt S, Sonden K, Plaza DF, Färnert A, Sundling C Cell Reports, Volume 39, Issue 3, 110709 (2022)
https://doi.org/10.1016/j.celrep.2022.110709

II. Integrated proteomics and single-cell transcriptomics reveal immune dynamics and severity markers in acute Plasmodium falciparum malaria Lautenbach MJ, Wyss K, Yman V, Foroogh F, Satarvandi D, Mousavian Z, Sonden K, Wang J, Bueno-Álevez M, Bergström S, Nilsson P, Edfors F, Brodin P, Uhlen M, Sundling C, Färnert A [Submitted]

III. The immunomodulatory effect of previous malaria exposure on monocytes and dendritic cells in acute P. falciparum infection Lautenbach MJ, Kleberg L, Courey-Ghaouzi AD, Serene Gower M, Sousa Silva C, Edfors F, Uhlen M, Färnert A, Sundling C [Manuscript]

IV. Elevated levels of Fc-receptor-like proteins during acute malaria are indicative of extensive B cell activation and long- lived antibody responses Lautenbach MJ, Kleberg L, Yman V, Tuju J, Edfors F, Osier FHA, Uhlén M, Färnert A, Sundling C [Manuscript]

V. Disease-specific plasma protein profiles in patients with fever after traveling to tropical areas Sundling C, Yman V, Mousavian Z, Angenendt S, Foroogh F, von Horn E, Lautenbach MJ, Grunewald J, Färnert A, Sonden K European Journal of Immunology 54:2350784 (2024)
https://doi.org/10.1002/eji.202350784