Ganusov, V. | bioRxiv Science

bioRxiv2019

Experimental Determination of the Force of Malaria Infection Reveals a Non-Linear Relationship to Mosquito Sporozoite Loads

Plasmodium sporozoites are the infective stage of the malaria parasite. Though this is a bottleneck for the parasite, the quantitative dynamics of transmission, from mosquito inoculation of sporozoites to patent blood-stage infection in the mammalian host, are poorly understood. Here we utilize a rodent model to determine the probability of malaria infection after infectious mosquito bite, and consider the impact of mosquito parasite load, blood-meal acquisition, probe-time, and probe location, on infection probability. We found that infection likelihood correlates with mosquito sporozoite load and, to a lesser degree, the duration of probing, and is not dependent upon the mosquitos ability to find blood. The relationship between sporozoite load and infection probability is non-linear and can be described by a set of models that include a threshold, with mosquitoes harboring over 10,000 salivary gland sporozoites being 7.5 times more likely to initiate a malaria infection. Overall, our data suggest that the small subset of highly infected mosquitoes may contribute disproportionally to malaria transmission in the field and that quantifying mosquito sporozoite loads could aid in predicting the force of infection in different transmission settings.\n\nAuthor SummaryMalaria is a leading cause of death in many parts of the world. Infection is initiated when infected Anopheles mosquitoes inject sporozoites as they look for blood. Though transmission is a bottleneck for the parasite and thus a good point for intervention, many aspects of transmission remain poorly understood. In this study, using a rodent model of malaria, we found that less than 20% of infectious bites result in disease, demonstrating that the majority of infective bites do not result in malaria infection. Furthermore, we found that the bites of mosquitoes with heavy parasite burdens are 7.5 times more likely to result in disease. These data have important implications for designing interventions targeting transmission stages of the malaria parasite as they suggest that reducing parasite loads, even without completely eliminating them, could be effective against disease spread. We also found that mosquitoes that probe but do not succeed in finding blood are equally likely to initiate infection, an important finding for human vaccine trials. Together, this work adds to our understanding of malaria transmission dynamics and our capacity to develop malaria elimination strategies.

microbiology↗

bioRxiv2019

Estimating residence times of lymphocytes in ovine lymph nodes

The ability of lymphocytes to recirculate between blood and secondary lymphoid tissues such as lymph nodes (LNs) and spleen is well established. Sheep have been used as an experimental system to study lymphocyte recirculation for decades and multiple studies exist documenting accumulation and loss of intravenously (i.v.) transferred lymphocytes in efferent lymph of various ovine LNs. Yet, surprisingly little work has been done to accurately quantify the dynamics of lymphocyte exit from the LNs and to estimate the average residence times of lymphocytes in ovine LNs. In this work we developed a series of mathematical models based on fundamental principles of lymphocyte recirculation in the body and specifically, on how lymphocytes enter and exit lymph nodes in non-inflammatory (resting) conditions. We fitted these models to data from several independent experiments. Our analysis suggested that in sheep, recirculating lymphocytes spend on average 3 hours in the spleen and 20 hours in skin or gut-draining LNs with a distribution of residence times in LNs following a skewed gamma (lognormal-like) distribution. The latter result is in contrast which recent suggestions that the distribution of residence times of naive T cells in murine LNs is exponential and that lymphocyte residence times depend on the LN type (e.g., gut- vs. skin-draining). Our mathematical models also suggested an explanation for a puzzling observation of the long-term persistence of i.v. transferred lymphocytes in the efferent lymph of the prescapular LN (pLN); the model predicted that this is a natural consequence of long-term persistence of the transferred lymphocytes in circulation. We also found that lymphocytes isolated from the skin-draining pLN have a two-fold increased entry rate into the pLN as opposed to the mesenteric (gut-draining) LN (mLN). Likewise, lymphocytes from mLN had a three-fold increased entry rate into the mLN as opposed to entry rate into pLN. Importantly, these cannulation data could not be explained by preferential retention of cells in LNs of origin. Taken together, our work illustrates the power of mathematical modeling in describing the kinetics of lymphocyte migration in sheep and provides quantitative estimates of lymphocyte residence times in ovine LNs.

immunology↗