Dysregulated Humoral Immunity to Nontyphoidal Salmonella in HIV-Infected African Adults

Abstract

Nontyphoidal Salmonellae are a major cause of life-threatening bacteremia among HIV-infected individuals. Although cell-mediated immunity controls intracellular infection, antibody protects against Salmonella bacteremia. We report that high titer antibodies specific for Salmonella lipopolysaccharide (LPS) associate with absent Salmonella-killing in HIV-infected African adults. Killing was restored by genetically shortening LPS from target Salmonella, or removing LPSspecific antibodies from serum. Complement-mediated killing of Salmonella by healthy serum is shown to be induced specifically by antibodies against outer membrane proteins. This killing is lost when excess antibody against Salmonella LPS is added. Thus our study indicates impaired immunity against nontyphoidal Salmonella bacteremia in HIV infection results from excess

Sensitivity and specificity of typhoid fever rapid antibody tests for laboratory diagnosis at two sub-Saharan African sites

“…This has been observed in patients infected with invasive non-typhoidal Salmonella (NTS). 27 This theoretical effect can also impair antibody binding in the TUBEX ® test, which is based on the O9 antigen. The production of antibodies against Salmonella lipopolysaccharide (LPS) is increased in patients with invasive NTS infection who are also HIVinfected.…”

IFN-γ–Producing CD4+ T Cells Promote Generation of Protective Germinal Center–Derived IgM+ B Cell Memory against Salmonella Typhi

“…Notably, Abs against porins (4,20) or against LPS (21) are associated with protective humoral immunity. For example, NTS porins elicit an immediate IgM response from B1b B cells that reduces bacterial titers in mice (22).…”

“…In humans, IgG and IgM Abs against pore-forming Omps (porins) can be found in individuals recovering from typhoid fever (15,16). Moreover, Abs directed against porins exert protective functions in HIV patients suffering from NTS infection (4). S. Typhi OmpC and OmpF can be purified and produced at large scale for application in humans (17).…”

“…The prevalence of Salmonella-related illness is particularly high in developing countries; however, because the number of travelers crossing international borders exceeds one billion people per year (3), the incidence of S. Typhi infection causing typhoid fever continues to increase in developed countries. Moreover, nontyphoidal Salmonella (NTS) serovars such as S. Typhimurium cause bacteremia in young children and immunologically compromised adults (4). Because S. Typhi and NTS serovars frequently persist in their hosts and thereby contribute to the transmission to naive individuals (5), these pathogens are considered important targets for vaccinationcontrolled diseases (6)(7)(8).…”

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“…Additionally, the accompanying loss in neutrophil chemoattraction results in absence of enteritis and further encourages Salmonella invasion (Gordon et al, 2002;Raffatellu et al, 2008). Secondly, there is humoral defect in which serum IgG antibodies directed against Salmonella inhibits the serum killing of NTS by other bacterial antibodies (MacLennan et al, 2010). Finally, a dysregulation in cellular cytokine production and attenuation of proinflammatory responses during intracellular infection encourages persistence as well as recurrence of invasive NTS (Feasey et al, 2012).…”