Impact of <scp><i>NLRP1</i> Met1154Val</scp> and <scp><i>IL1B</i></scp> variants on gestational malaria: an unexplored role of <scp>NLRP1</scp> in inflammasome activation by <i>Plasmodium</i> spp.

We hypothesized that variants in inflammasome-related genes could influence susceptibility to gestational malaria (GM). To test this, we conducted an association study in a cohort of pregnant women from a malaria-endemic region in northern Brazil, assessing whether specific functional single nucleotide variants (SNVs) in inflammasome genes affect (1) the response to Plasmodium infection and (2) the development of placental malaria. Our findings revealed that the NLRP1 p.Met1154Val variant was associated with a protective effect against Plasmodium infection. Moreover, IL1B SNVs appeared more prevalent in severe cases. Additionally, multivariate analyses incorporating placental blood cytokines, growth factors, and immunohistochemical features revealed that the NLRP1 p.Met1154Val variant correlated with a healthier placental state, highlighting a potential protective role of the NLRP1 inflammasome in GM. For the first time, we showed that infected red blood cells induce NLRP1- and caspase-1-dependent pyroptosis in BeWo trophoblast cells, identifying a novel inflammasome pathway involved in GM pathogenesis. Our study identifies a genetic variant underlying NLRP1 contribution to GM and suggests that NLRP1 may be an under-explored inflammasome receptor in malaria and infected erythrocytes' sensing. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.