# Systems approach identifies monocyte imbalance in symptomatic and asymptomatic P. vivax malaria

## TL;DR

The study shows that both symptomatic and asymptomatic P. vivax malaria impair monocyte function, challenging the idea that asymptomatic malaria is harmless.

## Contribution

The paper identifies monocyte imbalance as a novel feature of P. vivax malaria, both in symptomatic and asymptomatic cases.

## Key findings

- Symptomatic P. vivax malaria shows downregulation of monocyte-related transcripts and depletion of CCR2+CXCR4+ classical monocytes.
- Asymptomatic P. vivax infections also impair monocyte function despite supporting T-cell differentiation.
- The findings suggest asymptomatic malaria may not support full immune responses to control parasites or vaccines.

## Abstract

Although asymptomatic malaria was historically perceived as innocuous, emerging evidence revealed an immunosuppressive signature induced by asymptomatic Plasmodium falciparum infections. To examine if a similar process occurs in Plasmodium vivax malaria, we pursued a systems approach, integrating transcriptional profiling together with previously reported and novel mass cytometry phenotypes from individuals with symptomatic and asymptomatic P. vivax malaria. Symptomatic P. vivax malaria featured upregulation of anti-inflammatory pathways and checkpoint receptors. A profound downregulation of transcripts with roles in monocyte function was observed in symptomatic P. vivax malaria. This reduction in monocyte transcriptional activity was accompanied by a significant depletion of CCR2+CXCR4+ classical monocytes in symptomatic individuals. Despite allowing transcriptional profiles supporting T-cell differentiation, dysregulation of genes associated with monocyte activation and the inflammasome was also evident in individuals carrying P. vivax asymptomatic infections. Our results identify monocyte dysregulation as a key feature of the response to P. vivax malaria and support the concept that asymptomatic infection is not innocuous and might not support all immune processes required to eliminate parasitemia or efficiently respond to vaccination.

Symptomatic and low parasitemia asymptomatic Plasmodium vivax malaria feature transcriptional profiles consistent with impaired monocyte function. This reduction in transcriptional activity is aligned with the preferential depletion of CCR2+CXCR4+ classical monocytes from peripheral blood.

Asymptomatic malaria is thought to be beneficial to maintain clinical immunity and remains untreated.An important downregulation of pro-inflammatory pathways and monocyte-associated transcripts was observed during symptomatic P. vivax malaria.This reduction in monocyte transcriptional activity was associated with the preferential depletion of subsets of CD10+CCR2+CXCR4+ classical monocytes from peripheral blood.Whilst transcriptional profiles supporting T cell differentiation were enriched in asymptomatic P. vivax malaria, monocyte transcriptional activity was also impaired in these persistent infections of low parasite burden.The results suggest that asymptomatic malaria is not innocuous and might not support immune processes to fully control parasitemia or efficiently respond to malaria vaccines.

Asymptomatic malaria is thought to be beneficial to maintain clinical immunity and remains untreated.

An important downregulation of pro-inflammatory pathways and monocyte-associated transcripts was observed during symptomatic P. vivax malaria.

This reduction in monocyte transcriptional activity was associated with the preferential depletion of subsets of CD10+CCR2+CXCR4+ classical monocytes from peripheral blood.

Whilst transcriptional profiles supporting T cell differentiation were enriched in asymptomatic P. vivax malaria, monocyte transcriptional activity was also impaired in these persistent infections of low parasite burden.

The results suggest that asymptomatic malaria is not innocuous and might not support immune processes to fully control parasitemia or efficiently respond to malaria vaccines.

Symptomatic and low parasitemia asymptomatic Plasmodium vivax malaria feature transcriptional profiles consistent with impaired monocyte function. This reduction in transcriptional activity is aligned with the preferential depletion of CCR2+CXCR4+ classical monocytes from peripheral blood.