Figure 1: Anopheles mosquito, which is a vector that transmits Plasmodium falciparum.
Figure 2: Model for Vγ9Vδ2 γδ T cell response to Plasmodium falciparum.
The main focus of the Jagannathan lab has been studying mechanisms driving naturally acquired immunity to malaria. Children living in malaria endemic settings eventually develop “clinical” immunity to malaria – defined as an increasing proportion of Plasmodium falciparum (Pf) infections that are asymptomatic, although mechanisms driving this protection remain unclear.
We are actively studying how malaria drives innate immune dysfunction by studying the impact of in vivo and in vitro malaria infection on innate immune epigenetics, transcriptomics, and cellular function.
Researcher: Kassie Press
CD4+ T cells
We are in particular interested in how repeated malaria modulates the innate immune response and malaria-specific CD4+ T helper cells. We are also leveraging high-throughput sequencing approaches and pioneering new experimental and computational methods to study CD4+ T cell immunology and Pf-specific responses of these cells. Ongoing projects in the lab entail modeling CD4+ T cell epigenetics and clonal dynamics in children as they experience multiple Pf infections. Through this unique longitudinal study design, we hope to elucidate the role of CD4+ T cells in the acquisition of clinical immunity while also uncovering new biology with respect to memory recall responses and their heterogeneity within the CD4+ T cell compartment.
Researcher: Jason Nideffer
Natural Killer (NK) cells likely play an important role in immunity to malaria, but whether repeated malaria modifies the NK cell response remains unclear. We found that repeated malaria exposure was associated with expansion of an atypical, CD56neg population of NK cells that differed transcriptionally, epigenetically, and phenotypically from CD56dim NK cells, including decreased expression of PLZF and the Fc receptor g chain, increased histone methylation, and increased protein expression of LAG-3, KIR and LILRB1. CD56neg NK cells were highly functional, displaying greater antibody dependent cellular cytotoxicity than CD56dim NK cells, and higher frequencies of these cells were associated with protection against symptomatic malaria and high parasite densities. Importantly, following marked reductions in malaria transmission, frequencies of these cells rapidly declined, suggesting that continuous exposure to malaria is required to maintain this modified, adaptive-like NK cell subset.
Figure 3: Malaria Infection in Pregnancy (Harrington et al., 2018).
Placental malaria is a relatively understudied condition. The complexity of malaria immunology combined with a uniquely altered global immune landscape in pregnancy has made research in this area challenging, leaving one of the most vulnerable demographics in malaria-endemic countries medically neglected.
It has long been observed that birth outcomes improve with increased gravidity. This is also true of placental malaria: malaria-associated pregnancy complications and birth outcomes decrease in multigravid women living in malaria-endemic areas, suggesting adaptive immunity is an important contributor to this observed protective effect. By analyzing samples from multiple pregnancy cohorts, we can identify the mechanisms and cellular determinants that mediate protective immunity generally during malaria infection in pregnancy, and more specifically during placental malaria.
Our collaboration (IDRC, UCSF) is testing novel strategies to prevent malaria in pregnancy in order to improve birth outcomes. Leveraging samples from these clinical trials, we are studying the development of immunity against malaria in pregnancy, SARS-CoV-2 and malaria interactions, and as the impact of preventing malaria in pregnancy on immune responses during infancy.
Researchers: Adam Kirosingh, Alea Delmastro, Savannah Lewis, Nicholas Zehner, Karen Jacobson
One main objective within the lab and collaboration is evaluating novel, artemisinin-based chemoprevention to prevent malaria in children and during pregnancy. Our lab is particularly interested in how strategies to prevent malaria might alter the development of protective immunity to malaria.
During pregnancy, we seek to better understand the relationship between malaria chemoprevention and birth outcomes in endemic settings. By following pregnant patients receiving either standard-of-care or experimental chemopreventive antimalarials, we can evaluate the resulting impact on cellular and humoral immunity.
Given the profound global impact of the COVID-19 pandemic, we have applied our lab’s expertise to understanding host immune responses to SARS-CoV-2 infection.
COVID-19 study in North Americans
We are leveraging samples collected from the Lambda clinical trial to assess host immune responses to COVID-19, determine the immunologic impact of Lambda on SARS-CoV-2 specific immunity, and identify immunologic predictors of long COVID/Post-acute sequelae of COVID-19 (PASC).
Researchers: Karen Jacobson, Kattria van der Ploeg, Diego Martinez Mori, Daniel Ruiz Betancourt
COVID-19 and non-malarial febrile illnesses in Uganda
We are evaluating clinical outcomes of non-malarial febrile infections including SARS-CoV-2 in pregnancy in Ugandan women and infants enrolled in clinical trials of anti-malarial chemoprophylaxis.
Researchers: Karen Jacobson, Jordan John Lee
We are investigating differences in SARS-CoV-2-specific adaptive immune responses between North Americans (Lambda cohort) and Ugandans. We are investigating whether co-infections, like malaria, may impact the SARS-CoV-2-specific adaptive immune response and whether the immune system in Ugandans is “tolerated” or “trained” by underlying co-infections to respond to SARS-CoV-2 in a different manner compared to North Americans.
Researchers: Karen Jacobson, Kattria van der Ploeg, Adam Kirosingh
MainObjective: To test a novel therapeutic at Stanford – Peginterferon Lambda (Lambda), a type III interferon - for the treatment of SARS-CoV-2 infected patients (NCT 04331899). In this study, 120 SARS-CoV-2 infected patients with mild to moderate symptoms were randomized to receive Lambda vs. placebo, with peripheral blood collected at multiple timepoints following infection.
MainObjective: To broadly profile the immune systems of children and adults living in a malaria endemic area over multiple points in time and build state-of-the-art computational models of natural immunity to malaria.