Bactericidal Immunity to Salmonella in Africans and Mechanisms Causing Its Failure in HIV Infection

Goh, Yun Shan; Necchi, Francesca; O’Shaughnessy, Colette M.; Micoli, Francesca; Gavini, Massimiliano; Young, Stephen P.; Msefula, Chisomo; Gondwe, Esther N.; Mandala, Wilson L.; Gordon, Michael A.; Saul, Allan; MacLennan, Calman A.

doi:10.1371/journal.pntd.0004604

Cited by 22 publications

(24 citation statements)

References 39 publications

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“…This is likely to reflect an imbalance between the amounts of Ab present and the sheer number of O-Ag epitopes found on the bacterial surface, which can run into millions. Interestingly, a single isotype, IgG2, is sufficient to account for this inhibitory effect, yet this isotype is also known to be important for protection to encapsulated bacteria and after immunization with capsular polysaccharide vaccines ( 37 , 38 , 40 , 41 ). In addition to this there may be a role for the actual frequency that Ag is found.…”

Section: Discussionmentioning

confidence: 99%

IgG1 Is Required for Optimal Protection after Immunization with the Purified Porin OmpD from Salmonella Typhimurium

Zhang

Domínguez-Medina

Cumley

et al. 2017

The Journal of Immunology

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In mice, the IgG subclass induced after Ag encounter can reflect the nature of the Ag. Th2 Ags such as alum-precipitated proteins and helminths induce IgG1, whereas Th1 Ags, such as Salmonella Typhimurium, predominantly induce IgG2a. The contribution of different IgG isotypes to protection against bacteria such as S. Typhimurium is unclear, although as IgG2a is induced by natural infection, it is assumed this isotype is important. Previously, we have shown that purified S. Typhimurium porins including outer membrane protein OmpD, which induce both IgG1 and IgG2a in mice, provide protection to S. Typhimurium infection via Ab. In this study we report the unexpected finding that mice lacking IgG1, but not IgG2a, are substantially less protected after porin immunization than wild-type controls. IgG1-deficient mice produce more porin-specific IgG2a, resulting in total IgG levels that are similar to wild-type mice. The decreased protection in IgG1-deficient mice correlates with less efficient bacterial opsonization and uptake by macrophages, and this reflects the low binding of outer membrane protein OmpD–specific IgG2a to the bacterial surface. Thus, the Th2-associated isotype IgG1 can play a role in protection against Th1-associated organisms such as S. Typhimurium. Therefore, individual IgG subclasses to a single Ag can provide different levels of protection and the IgG isotype induced may need to be a consideration when designing vaccines and immunization strategies.

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Section: Discussionmentioning

confidence: 99%

IgG1 Is Required for Optimal Protection after Immunization with the Purified Porin OmpD from Salmonella Typhimurium

Zhang

Domínguez-Medina

Cumley

et al. 2017

The Journal of Immunology

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“…Although the association between HIV and iNTS disease is well established, the underlying mechanisms of HIV infection as a determinant of mortality in children with iNTS disease has not been well explored. Immunological defects in HIV-infected adults leading to susceptibility to iNTS disease include impaired gut mucosal immunity [ 48 ], and dysregulated cellular [ 49 ] and humoral immunity [ 50 , 51 ]. The mechanisms that contribute to increased mortality in children with iNTS disease and HIV provide important questions for future research, which should explore the key interaction of HIV infection and malnutrition [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

Presentation of life-threatening invasive nontyphoidal Salmonella disease in Malawian children: A prospective observational study

et al. 2017

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Nontyphoidal Salmonellae commonly cause invasive disease in African children that is often fatal. The clinical diagnosis of these infections is hampered by the absence of a clear clinical syndrome. Drug resistance means that empirical antibiotic therapy is often ineffective and currently no vaccine is available. The study objective was to identify risk factors for mortality among children presenting to hospital with invasive Salmonella disease in Africa. We conducted a prospective study enrolling consecutive children with microbiologically-confirmed invasive Salmonella disease admitted to Queen Elizabeth Central Hospital, Blantyre, in 2006. Data on clinical presentation, co-morbidities and outcome were used to identify children at risk of inpatient mortality through logistic-regression modeling. Over one calendar year, 263 consecutive children presented with invasive Salmonella disease. Median age was 16 months (range 0–15 years) and 52/256 children (20%; 95%CI 15–25%) died. Nontyphoidal serovars caused 248/263 (94%) of cases. 211/259 (81%) of isolates were multi-drug resistant. 251/263 children presented with bacteremia, 6 with meningitis and 6 with both. Respiratory symptoms were present in 184/240 (77%; 95%CI 71–82%), 123/240 (51%; 95%CI 45–58%) had gastrointestinal symptoms and 101/240 (42%; 95%CI 36–49%) had an overlapping clinical syndrome. Presentation at <7 months (OR 10.0; 95%CI 2.8–35.1), dyspnea (OR 4.2; 95%CI 1.5–12.0) and HIV infection (OR 3.3; 95%CI 1.1–10.2) were independent risk factors for inpatient mortality. Invasive Salmonella disease in Malawi is characterized by high mortality and prevalence of multi-drug resistant isolates, along with non-specific presentation. Young infants, children with dyspnea and HIV-infected children bear a disproportionate burden of the Salmonella-associated mortality in Malawi. Strategies to improve prevention, diagnosis and management of invasive Salmonella disease should be targeted at these children.

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“…Although secretory IgA activates the mannan-binding lectin pathway ( 43 ), depletion of IgA from our samples did not significantly affect bactericidal activity. In studies examining the role of bactericidal activity against NTS in African adults with or without HIV infection, bactericidal activity was not seen with anti-O:LPS IgA and the bactericidal properties of sera depended on the relative titers of anti-O:LPS isotypes so that high titers of IgA antibodies correlated with absence of bactericidal activity ( 37 , 44 ). Other mechanisms may be at play for the absence of protection from typhoid challenge we observed.…”

Section: Discussionmentioning

confidence: 99%

Salmonella Typhi Bactericidal Antibodies Reduce Disease Severity but Do Not Protect against Typhoid Fever in a Controlled Human Infection Model

et al. 2018

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Effective vaccines against Salmonella Typhi, a major cause of febrile illness in tropical regions, can have a significant effect as a disease control measure. Earlier work has shown that immunization with either of two Salmonella Typhi vaccines, licensed Ty21a or candidate M01ZH09, did not provide full immunity in a controlled human infection model. Here, we describe the human humoral immune responses to these oral vaccines and their functional role in protection after challenge with S. Typhi. Serum, obtained from healthy volunteers before and after vaccination with Ty21a or M01ZH09 or placebo and before and after oral challenge with wild-type S. Typhi, was assessed for bactericidal activity. Single-dose vaccination with M01ZH09 induced an increase in serum bactericidal antibodies (p = 0.001) while three doses of Ty21a did not. No association between bactericidal activity and protection against typhoid after challenge was seen in either vaccine arm. Bactericidal activity after vaccination correlated significantly with delayed disease onset (p = 0.013), lower bacterial burden (p = 0.006), and decreased disease severity scores (p = 0.021). Depletion of antibodies directed against lipopolysaccharide significantly reduced bactericidal activity (p = 0.009). We conclude that antibodies induced after ingestion of oral live-attenuated typhoid vaccines or after challenge with wild-type S. Typhi exhibit bactericidal activity. This bactericidal activity is mediated by anti-O:LPS antibodies and significantly reduces clinical symptoms but does not provide sterile immunity. This directs future vaccine studies toward other antigens or mechanisms of protection against typhoid.

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Bactericidal Immunity to Salmonella in Africans and Mechanisms Causing Its Failure in HIV Infection

Cited by 22 publications

References 39 publications

IgG1 Is Required for Optimal Protection after Immunization with the Purified Porin OmpD from Salmonella Typhimurium

IgG1 Is Required for Optimal Protection after Immunization with the Purified Porin OmpD from Salmonella Typhimurium

Presentation of life-threatening invasive nontyphoidal Salmonella disease in Malawian children: A prospective observational study

Salmonella Typhi Bactericidal Antibodies Reduce Disease Severity but Do Not Protect against Typhoid Fever in a Controlled Human Infection Model

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