Immunological effects of asymptomatic vibrio cholerae, salmonella enterica serovar typhi and entamoeba histolytica enteric pathogens during HIV infection and exposure.
Year: 2017
Type: dissertation
Abstract: Background \nAsymptomatic infection by enteric pathogens has been attributed to causing several outbreaks in the \nworld. Common pathogens in this category are Vibrio cholerae, Salmonella typhi and Entamoeba \nhistolytica infection of pregnant and lactating mothers. Exposure of the infant and the immune \nresponse during the early developmental years requires investigation. In the era of high HIV burden \nand the introduction of HIV prevention of mother to child transmission (PMTCT), many infants are \nexposed to these pathogens yet remain uninfected, however still face the challenge of high morbidity \nand mortality as compared to their unexposed and uninfected counterparts. The cause of such an \nanomaly has not been fully investigated. \nAim \nThe aim of this study is to investigate the burden and the immunological effect of asymptomatic \nenteric pathogen carriage in pregnant mothers, both HIV-infected and HIV-uninfected, and their \ninfants in a high HIV burdened population of Harare, Zimbabwe. \nMethodology \nThe study was a purposive cross-sectional sub-study in a birth cohort established at the University \nof Zimbabwe, College Of Health Sciences (UZ-CHS Birth Cohort). Participants were from the highdensity suburbs of Glenview, Kuwadzana and Dzivarasekwa. These suburbs were previously \naffected by the 2008 cholera epidemic as well as the 2012 typhoid outbreak that hit Harare, \nZimbabwe. HIV rapid testing was performed at enrolment for mothers unaware of their HIV status \nor those who wanted HIV re-testing for various personal reasons. Those HIV infected with \ndocumented HIV status were asked to provide the evidence and were not re-tested. \nThe HIV status of neonates was ascertained using nucleic acid-based testing at the National Early \nInfant Diagnostic (EID) department based at the National Microbiology Reference Laboratory in \nHarare, Zimbabwe. The test made use of the Dried Blood Spot (DBS) samples collected from the \ninfants at various time points. \nA total of 417 pregnant mothers were recruited based on their consent to provide stool samples, \nblood and urine for both the mother at recruitment and the infant upon delivery. A questionnaire to \ncollect information on socio-demographic, clinical, delivery, water and sanitation, diarrheal history \nincluding antibiotic use, concurrent TB infections, ART regimen, planned baby feeding method, \ndiet as well as nutritional data on probiotic uptake was administered to the mothers. Of the 417 \nmothers, only 204 mothers and 308 infants provided stool samples, which were cultured for enteric \npathogens targeting Salmonella entrica serovar Typhi (S. typhi) and Vibrio cholerae, although in \nthe process any non-lactose fermenter identified was considered a potential pathogen hence were \nfurther identified using an Analytical Profile Index (API; Biomerieux: France) and included in the \nstudy. The stool samples were also used for antigen ELISA targeting Entamoeba histolytica (E. \nhistolytica) infection. \nThe microbial results were used to calculate the prevalence of S. typhi, V. cholerae and E. histolytica \nin the study population. Data was analysed using STATA 13 analytical software. For further analysis \non immunological factors in mother-infant pairs (MIPs), only paired mothers were included based \non stool as well as plasma availability and the outcome of culture and ELISA results. Multiplex \nimmunoassay utilised a 27-plex (IL-1β, IL-1r, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL12p70, IL-13, IL-15, IL-17a, Eotaxin, basic PDGF, G-CSF, GM-CSF, IFN-, IP-10, MCP1(MCAF), MIP-1α, MIP-1β , PDGF-BB, RANTES, TNF- α and VEGF) cytokine profile and a 6- \nplex isotyping (immunoglobulin: IgG1, IgG2, IgG3, IgG4, IgM and IgA) assay. Immunological \nassays were performed on the 39 MIPs purposively selected based on the culture outcomes as \ndescribed, using BioRad Luminex machine according to manufacturer’s instruction \nBased on the cytokine and immunoglobulin concentrations, maternal characteristics influencing \ninfant cytokine and immunoglobulin production were analysed. \nResults \nThe presence of V. cholerae nor S. typhi was detected but E. histolytica prevalence in mothers was \ncalculated at 5.4% while in infants it was 5.6%. There was no significant difference in the prevalence \nof E. histolytica between HIV-infected and HIV-uninfected mothers (p=0.318) as well as between \nHIV-exposed uninfected and HIV-unexposed uninfected infants (p=0.056). E. histolytica infection \nwas only noted in 1 HIV-uninfected mother-neonate pair. The resistance to 3rd generation \ncephalosporines in the non-lactose fermenting bacterial isolates was detected. \nThe cytokine groups of IL-1r, IL-4, IL-9, IL-12p70, IL-17a, G-CSF and PDGF-BB were \nsignificantly raised in E. histolytica infected compared to non-infected lactating mothers (p<0.05). \nIn babies, E. histolytica carriage had no significant effect on the cytokine and immunoglobulin \nconcentration. In this study maternal E. histolytica carriage was significantly (p=0.026) correlated \nwith infant Interleukin-12p70 (IL-12p70; p<0.026), Fibroblast Growth Factor-basic (FGF-basic; \np<0.026), Granulocyte Monocyte-Colony Stimulating Factor (GM-CSF; p<0.026) and Tumor \nNecrosis Factor (TNF; p<0.026)-α. The odds ratio of passing high levels of these cytokines to infants \nis reduced by 86% if the mother is a carrier of E. histolytica during pregnancy (OR: 0.14). Carriage \nof any form of enteric infection such as Non-lactose fermenters (NLFs) including E. histolytica \nsignificantly increased the levels of IL-1r, IL-4, IL-9, IL-10, IL-12p70, IL17a, G-CSF, GM-CSF, \nIFN-, PDGF-BB and TNF-α cytokines (p<0.05). \nHowever, no significant difference in immunoglobulin levels was noted amongst the mothers. IL13 and G-CSF levels were significantly raised in HIV-infected compared to HIV-uninfected \nlactating mothers (p=0.0389 and p=0.0324, respectively). \nIgA immunoglobulin levels were significantly raised among HIV-exposed uninfected than HIVunexposed uninfected infants. It has also been observed that maternal E. histolytica carriers are \nsignificantly more likely to have infants with low levels of IL-12p70, FGF-basic, GM-CSF and \nTNF-α cytokines and high levels of IgA immunoglobulin. HIV-infected mothers are significantly \nmore likely to have infants with low levels of IgG2 and IgA immunoglobulins. \nMothers giving birth at a mean age above 30.38 ±STD 6.09 years are more likely to have infants \nwith low IgG4 levels (p=0.050). Maternal HIV infection influences infant IgG2 and IgA \nimmunoglobulin levels. Also, a maternal age of >30years reduces the odds ratio of passing high \nIgG4 to the infant (p=0.050). Maternal HIV infection influences infant IgG2 and IgA \nimmunoglobulin levels. Infants born to HIV positive mothers are significantly associated (p=0.049) \nwith lower odds of having high IgG2 levels, ie., reduced by 76% in infants born to HIV-infected \nmothers compared to those born to HIV-uninfected mothers. Similarly, an infant born to a HIVinfected mother is significantly associated (p=0.035) with lower odds of having high IgA \nimmunoglobulin levels compared to those born to HIV-uninfected mothers (OR: 0.22). \nUnderweight/small to gestational age (SGA) babies (birth weight <2500g) were found to have \nsignificantly raised IL-7 cytokine levels compared to normal for gestational age (NGA) babies \nwhose birth weight was >2500g (p=0.0149). \nConclusion \nAsymptomatic enteric E. histolytica carriage is a reality in pregnant women and their neonates with \nthe possibility of congenital transmission. We confirm that there is no V. cholerae carriage in \nGlenview, Dzivarasekwa and Kuwadzana, areas affected in the 2008 cholera epidemic in \nZimbabwe. Moreover, there was no evidence of S. typhi carriage in these suburbs following the \ndevastating 2012 typhoid outbreak. This study reports an expansive pro-inflammatory cytokine and \nchemokine profile that is up-regulated in lactating mothers with asymptomatic enteric pathogens. \nHIV exposure had no effect on baby cytokine profiles. The importance of IL-7 in neonates requires \nfurther investigation as it might assist in reducing the prevalence of small for gestational age (SGA) \nbabies. \nSignificance and impact of study \nOur study culminates in the need to consider maternal characteristics such as age, HIV status and \nenteric pathogen carriage in pregnancy as these might impact on the infants’ immune responses. \nThis will assist in the decisions on disease treatment and management of pregnant women and \ninfants. The study findings also assist in developing effective immunotherapy in E. histolytica and \nHIV exposures and infections in an effort to promote maternal and child health.
Author: Agness Farai Nhidza
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W3020968423