Loss of Humoral and Cellular Immunity to Invasive Nontyphoidal Salmonella during Current or Convalescent Plasmodium falciparum Infection in Malawian Children.

Tonney S Nyirenda,Chisomo L Msefula,Janet Storm,Robert S Heyderman,James T Nyirenda,Queen Dube,Dumizulu L Tembo,Melita A Gordon,Kondwani C Jambo,Wilson L Mandala,Henry C Mwandumba,David W Pascual

doi:10.1128/cvi.00057-17

Abstract

ABSTRACTInvasive nontyphoidal Salmonella (iNTS) infections are commonly associated with Plasmodium falciparum infections, but the immunologic basis for this linkage is poorly understood. We hypothesized that P. falciparum infection compromises the humoral and cellular immunity of the host to NTS, which increases the susceptibility of the host to iNTS infection. We prospectively recruited children aged between 6 and 60 months at a Community Health Centre in Blantyre, Malawi, and allocated them to the following groups; febrile with uncomplicated malaria, febrile malaria negative, and nonfebrile malaria negative. Levels of Salmonella enterica serovar Typhimurium-specific serum bactericidal activity (SBA) and whole-blood bactericidal activity (WBBA), complement C3 deposition, and neutrophil respiratory burst activity (NRBA) were measured. Levels of SBA with respect to S. Typhimurium were reduced in febrile P. falciparum-infected children (median, −0.20 log10 [interquartile range {IQR}, −1.85, 0.32]) compared to nonfebrile malaria-negative children (median, −1.42 log10 [IQR, −2.0, −0.47], P = 0.052). In relation to SBA, C3 deposition on S. Typhimurium was significantly reduced in febrile P. falciparum-infected children (median, 7.5% [IQR, 4.1, 15.0]) compared to nonfebrile malaria-negative children (median, 29% [IQR, 11.8, 48.0], P = 0.048). WBBA with respect to S. Typhimurium was significantly reduced in febrile P. falciparum-infected children (median, 0.25 log10 [IQR, −0.73, 1.13], P = 0.0001) compared to nonfebrile malaria-negative children (median, −1.0 log10 [IQR, −1.68, −0.16]). In relation to WBBA, S. Typhimurium-specific NRBA was reduced in febrile P. falciparum-infected children (median, 8.8% [IQR, 3.7, 20], P = 0.0001) compared to nonfebrile malaria-negative children (median, 40.5% [IQR, 33, 65.8]). P. falciparum infection impairs humoral and cellular immunity to S. Typhimurium in children during malaria episodes, which may explain the increased risk of iNTS observed in children from settings of malaria endemicity. The mechanisms underlying humoral immunity impairment are incompletely understood and should be explored further.

Highlights

Invasive nontyphoidal Salmonella infections, principally by Salmonella enterica serovar Typhimurium and S. enterica serovar Enteritidis, are estimated to cause over 2.1 million illnesses and 416,000 deaths per year [1]
We have previously shown that acquisition of serum bactericidal activity (SBA) with respect to S
This study extended our understanding of how P. falciparum infection compromises phagocyte-dependent immunity to NTS in children [16,17,18] and provided an additional explanation for the observed increased susceptibility of children to Invasive nontyphoidal Salmonella (iNTS) in settings of malaria endemicity

Summary

Introduction

Invasive nontyphoidal Salmonella (iNTS) infections, principally by Salmonella enterica serovar Typhimurium and S. enterica serovar Enteritidis, are estimated to cause over 2.1 million illnesses and 416,000 deaths per year [1]. Phagocytes (including neutrophils and monocytes) are key players in controlling rapid replicating NTS within the gut mucosa and in preventing the spread of NTS to systemic organs [15] Studies in both humans and mice have shown that P. falciparum-derived products such as hemozoin, heme, and heme oxygenase-1 mediate the reduction in phagocytosis and oxidative burst activities [16,17,18]. The anti-inflammatory environment, coupled with reduced levels of phagocytosis and oxidative burst activities during malaria, is thought to create a favorable setting for NTS replication within the gut mucosa and bloodstream compartments. Typhimurium in addition to the impairment of the respiratory burst of phagocytes which was known before, providing a comprehensive explanation for the increased susceptibility to iNTS seen in children during malaria

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