Biology subjects

Camara, M.

Publications and source records attributed to Camara, M..

14 recordsLinked to original sources

bioRxiv2025

A SHERLOCK toolbox for the eco-epidemiological surveillance of animal African trypanosomosis reveals a similar parasite diversity in domestic pigs in two ancient sleeping sickness foci in Western Africa.

Animal African trypanosomosis (AAT), caused by protist parasites of the genus Trypanosoma, puts upward of a million head of livestock at risk across 37 countries in Africa. The economic impact of AAT and the presence of human-infectious trypanosomes in animals place a clear importance on improving diagnostics for animal trypanosomes to map the distribution of the veterinary parasites and identify reservoirs of human-infectious trypanosomes. We have adapted the CRISPR-based detection toolkit SHERLOCK (Specific High-sensitivity Enzymatic Reporter unLOCKing) for trypanosomatid parasites responsible for AAT (SHERLOCK4AAT) including Pan- trypanosomatid, Trypanozoon, T. vivax, T. congolense, T. theileri, T. simiae and T. suis assays. To test the applicability of this technique in the field, we analysed dried blood spots collected from 200 farm and 224 free-ranging pigs in endemic and historical human African trypanosomiasis foci in Guinea and Cote dIvoire, respectively. The results revealed that SHERLOCK4AAT can detect and discriminate between trypanosome species involved in multiple infections with a high sensitivity. 62.7 % [58.1, 67.3] of pigs were found infected with at least one trypanosome species. T. brucei gambiense, a human-infectious trypanosome, was found in one animal at both sites, highlighting the risk that these animals may act as persistent reservoirs. These data suggest that, due to their proximity to humans and their attractiveness to tsetse flies, pigs could act as sentinels to monitor T. b. gambiense circulation using the SHERLOCK4AAT toolbox.

microbiology↗

bioRxiv2024

The Quorum Sensing regulated sRNA Lrs1 is involved in the adaptation to low iron in Pseudomonas aeruginosa

Iron is an essential nutrient for microbial growth. The opportunistic pathogen Pseudomonas aeruginosa can survive under diverse conditions, including iron-depleted environments with the aid of small non-coding RNAs (sRNAs). P. aeruginosa also uses three quorum sensing (QS) systems Las, Rhl, and Pqs to coordinate virulence and infection establishment at the population level. This study links the sRNA Lrs1, which is located within the promoter of the Pqs biosynthetic operon pqsABCDE, to iron uptake regulation in the P. aeruginosa strain PAO1-L. Transcriptomics and phenotypic assays indicate that Lrs1 downregulates the production of the siderophore pyochelin but not pyoverdine, and that lrs1 regulation itself is dependent on iron availability. Although Lrs1 has been implicated in a positive feedback loop with the transcriptional regulator LasR in the strain PA14, the present findings indicate that this is not the case in PAO1-L in the tested conditions. Transcription of Lrs1 is dependent on quorum sensing, predominantly on RhlR with an auxiliary effect by PqsE. Furthermore, the Pqs system and phenazine production are modulated by Lrs1 only under iron limitation. This study identifies Lrs1 as a new QS-dependent post-transcriptional regulator of iron uptake and virulence highlighting its importance in environmental adaptation in P. aeruginosa. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=74 SRC="FIGDIR/small/627364v1_ufig1.gif" ALT="Figure 1"> View larger version (12K): org.highwire.dtl.DTLVardef@1585ca5org.highwire.dtl.DTLVardef@2a7d55org.highwire.dtl.DTLVardef@18a712eorg.highwire.dtl.DTLVardef@c84d2_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2023

Population genetics of Glossina palpalis gambiensis in the sleeping sickness focus of Boffa (Guinea) before and after eight years of vector control: no effect of control despite a significant decrease of human exposure to the disease

Human African trypanosomosis (HAT), also known as sleeping sickness, is still a major concern in endemic countries. Its cyclical vector are biting insects of the genus Glossina or tsetse flies. In Guinea, the mangrove ecosystem contains the main HAT foci of Western Africa. There, the cyclical vector is Glossina palpalis gambiensis. A still ongoing vector control campaign (VCC) started in 2011 in the focus of Boffa, using tiny targets, with a 79% tsetse density reduction in 2016 and significant impact on the prevalence of the disease (from 0.3% in 2011 to 0.11% in 2013, 0.0352% in 2016 and 0.0097% in 2019). To assess the sustainability of these results, we have studied the impact of this VCC on the population biology of G. p. gambiensis in Boffa. We used the genotyping at 11 microsatellite markers and population genetic tools of tsetse flies from different sites and at different dates before and after the beginning of the VCC. In variance with a significant impact of VCC on the apparent densities of flies captured in the traps deployed, the global population of G. p. gambiensis displayed no variation of the sex-ratio, no genetic signature of control, and behaved as a very large population occupying the entire zone. This implies that targets deployment efficiently protected the human populations locally, but did not impact tsetse flies where targets cannot be deployed and where the main tsetse population exploits available resources. We thus recommend the pursuit of vector control measures with the same strategy, through the joint effect of VCC and medical surveys and treatments, in order to protect human populations from HAT infections until the disease can be considered as entirely eradicated from the focus.

evolutionary biology↗

bioRxiv2022

Interleukin-17 drives sex-dependent weight loss and changes in feeding behaviour during Trypanosoma brucei infection

In the skin, Trypanosoma brucei colonises the subcutaneous white adipose tissue (scWAT) and harbours a pool of parasites that are proposed to be competent for forward transmission. The interaction between parasites, adipose tissue, and the local immune system is likely to drive the adipose tissue wasting and weight loss observed in cattle and humans infected with T. brucei. However, mechanistically, the events leading to scWAT wasting are not fully understood. Here, using several complementary approaches, including mass cytometry by time of flight, bulk and single cell transcriptomics, and in vivo genetic models, we found that T. brucei infection drives local expansion of several IL-17A-producing cells in the murine WAT, including TH17 and V{gamma}6+ T cells. We also found that global IL-17 deficiency, or mice lacking IL-17 receptor expression exclusively in adipocytes, were protected from infection-induced WAT wasting and weight loss. Unexpectedly, we found that abrogation of IL-17 signalling in adipocytes results in a significant accumulation of Dpp4+ Pi16+ interstitial preadipocytes and a higher burden of extravascular parasites in the WAT, highlighting a critical role for IL-17 signalling in controlling preadipocyte fate, scWAT tissue dynamics, and local parasite burden. Taken together, our study highlights the central role of adipocyte IL-17 signalling in controlling WAT responses to infection, suggesting that adipocytes are a critical coordinator of the tissue dynamics and immune responses to T. brucei infection.

immunology↗

bioRxiv2022

Molecular characterization of extended-spectrum beta-lactamase-producing extra-intestinal pathogenic Escherichia coli isolated in a university teaching hospital Dakar-Senegal

Extra-intestinal pathogenic Escherichia coli (ExPEC), a predominant Gram-negative bacterial pathogen, express a wide range of virulence factors and is responsible of several diseases including urinary tract infections (UTI), nosocomial pneumonia, bacteremia, and neonatal meningitis. ExPEC isolates are often multidrug resistant (MDR) and clones producing extended-spectrum beta-lactamases (ESBL) are increasingly reported all over the world. Seventy-eight clinical ExPEC strains were selected for this study. The majority was from UTIs (n=51), while the rest (n=27) was from pus, sputum, bronchial fluid and vaginal samples (non-uropathogenic ExPEC). Interestingly, 49 out of the 78 ExPEC isolates where considered as community-acquired (CA) and 29 hospital-acquired (HA) bacteria. Antibiotic susceptibility testing was performed using the Kirby-Bauer disc diffusion method. Standard polymerase chain reaction (PCR) was used to screen major ESBL genes (blaCTX-M, blaOXA-1, blaTEM, blaSHV) and blaCTX-M variants (blaCTX-M-1, blaCTX-M-9, blaCTX-M-15, blaCTX-M-25). All the ExPEC strains were resistant to ampicillin, ticarcillin, amoxicillin/clavulanic acid combination, cefalotin, cefotaxime, ceftazidime, cefepime and aztreonam, but showed a high susceptibity to fosfomycin (98.7%, n = 77), ertapenem (96.2%, n = 75), and imipenem (100%). Moreover, isolates harbored at least one ESBL gene, including blaCTX-M (98.7%), blaOXA-1 (78.2%), blaTEM (44.9%) and blaSHV (3.8%). The CTX-M variants were also found with the predominance of blaCTX-M-1 (90.9%) and blaCTX-M-15 (90.9%) followed by blaCTX-M-9 (11.7%), while blaCTX-M-25 was not detected. Despite the resistance to most of the tested antibiotics, ExPEC isolates showed fortunately a good susceptibility to fosfomycin and carbapenems. blaCTX-M (blaCTX-M1, blaCTX-M15) and blaOXA-1 seem to be E. coli major ESBL genes circulating in Senegal. No significant difference was noted when comparing prevalence of ESBL genes detected from CA and HA strains, and from UPEC and non-uropathogenic ExPEC. The high level of resistance to antimicrobials observed stresses the need of establishing an epidemiological surveillance of antimicrobial resistance in both community and hospital settings.

microbiology↗

bioRxiv2022

Culture and genomic analysis of Symbiopectobacterium purcellii, gen.nov. sp. nov., isolated from the leafhopper Empoasca decipiens

Bacterial endosymbionts are found in multiple arthropod species, where they play crucial roles as nutritional symbionts, defensive symbionts or reproductive parasites. Recent work has highlighted a new clade of heritable microbes within the gammaproteobacteria that enter into both obligate and facultative symbioses, with an obligately required unculturable symbiont recently given the name Cand. Symbiopectobacterium. In this study, we describe a culturable rod shaped non-flagellated bacterial symbiont from this clade isolated from the leafhopper Empoasca decipiens. The symbiont is related to the transovarially-transmitted BEV bacterium that was first isolated from the leafhopper Euscelidius variegatus by Alexander Purcell, and we therefore name the symbiont Symbiopectobacterium purcellii sp. nov. gen. nov. We further report the closed genome sequence for S. purcellii. The genome is atypical for a heritable microbe, being large in size, without profound AT bias and with little evidence of pseudogenization. The genome is predicted to encode Type II, III and VI secretion systems and associated effectors and a non-ribosomal peptide synthase array likely to produce bioactive small molecules. Predicted metabolism is more complete than for other symbionts in the Symbiopectobacterium clade, and the microbe is predicted to synthesize a range of B vitamins. However, Biolog plate analysis indicate metabolism is depauperate compared to the sister clade, represented by Pectobacterium carotovorum. A quorum-sensing pathway related to that of Pectobacterium spp. (containing an overlapping expI-expR1 pair in opposite directions and a "solo" expR2) is evidenced, and LC-MS/MS analysis reveals the presence of 3-hydroxy-C10-HSL as the sole N-acylhomoserine lactone (AHL) in our strain. This AHL profile is profoundly divergent from that of other Erwinia and Pectobacterium spp., which produce mostly 3-oxo-C6- and 3-oxo-C8-HSL and could aid group identification. Thus, this microbe denotes one that has lost certain pathways associated with a saprophytic lifestyle but represents an important baseline against which to compare other members of the genus Symbiopectobacterium that show more profound integration into host biology.

microbiology↗

bioRxiv2021

Disruption of the Pseudomonas aeruginosa Tat system perturbs PQS-dependent quorum sensing and biofilm maturation through loss of the Rieske cytochrome bc1 sub-unit

Extracellular DNA (eDNA) is a major constituent of the extracellular matrix of Pseudomonas aeruginosa biofilms and its release is regulated via the pseudomonas quinolone signal (PQS) dependent quorum sensing (QS). By screening a P. aeruginosa transposon library to identify factors required for DNA release, mutants with insertions in the twin-arginine translocation (Tat) pathway were identified as exhibiting reduced eDNA release, and defective biofilm architecture with enhanced susceptibility to tobramycin. P. aeruginosa tat mutants showed substantial reductions in pyocyanin, rhamnolipid and membrane vesicle (MV) production consistent with perturbation of 2-heptyl-3-hydroxy-4-quinolone (PQS) dependent QS as demonstrated by changes in pqsA expression and 2-alkyl-4-quinolone (AQ) production. Provision of exogenous PQS to the tat mutants did not return pqsA, rhlA or phzA1 expression or pyocyanin production to wild type levels. However, transformation of the tat mutants with the AQ-independent pqs effector pqsE restored phzA1 expression and pyocyanin production. Since mutation or inhibition of Tat prevented PQS-driven auto-induction, we sought to identify the Tat secretion substrate responsible. A pqsA::lux fusion was introduced into each of 34 validated P. aeruginosa Tat substrate deletion mutants. Analysis of each mutant for reduced bioluminescence revealed that the signalling defect was associated with the Rieske iron-sulfur subunit of the cytochrome bc1 complex. In common with the parent strain, a Rieske mutant exhibited defective PQS signalling, AQ production, rhlA expression and eDNA release that could be restored by genetic complementation. Thus, lack of the Rieske sub-unit export is clearly responsible for the Tat-mediated perturbation of PQS-dependent QS, the loss of virulence factor production, biofilm eDNA and the tobramycin tolerance of P. aeruginosa biofilms. Author SummaryPseudomonas aeruginosa is a highly adaptable human pathogen responsible for causing chronic biofilm-associated infections. Biofilms are highly refractory to host defences and antibiotics and thus difficult to eradicate. The biofilm extracellular matrix incorporates extracellular DNA (eDNA). This stabilizes biofilm architecture and helps confer tolerance to antibiotics. Since mechanisms that control eDNA release are not well understood, we screened a P. aeruginosa mutant bank for strains with defects in eDNA release and discovered a role for the twin-arginine translocation (Tat) pathway that exports folded proteins across the cytoplasmic membrane. Perturbation of the Tat pathway resulted in defective biofilms susceptible to antibiotic treatment as a consequence of perturbed pseudomonas quinolone (PQS) signalling. This resulted in the failure to produce or release biofilm components including eDNA, phenazines and rhamnolipids as well as microvesicles. Furthermore, we discovered that perturbation of PQS signalling was a consequence of the inability of tat mutants to translocate the Rieske subunit of the cytochrome bc1 complex involved in electron transfer and energy transduction. Given the importance of PQS signalling and the Tat system to virulence and biofilm maturation in P. aeruginosa, our findings underline the potential of the Tat system as a drug target for novel antimicrobial agents.

microbiology↗

bioRxiv2020

NirA is an alternative nitrite reductase from Pseudomonas aeruginosa with potential as an anti-virulence target

The opportunistic pathogen Pseudomonas aeruginosa produces an arsenal of virulence factors causing a wide range of diseases in multiple hosts and is difficult to eradicate due to its intrinsic resistance to antibiotics. With the antibacterial pipeline drying up, anti-virulence therapy has become an attractive alternative strategy to the traditional use of antibiotics to treat P. aeruginosa infections. To identify P. aeruginosa genes required for virulence in multiple hosts, a random library of Tn5 mutants in PAO1-L was previously screened in vitro for those showing pleiotropic effects in the production of virulence phenotypes. Using this strategy, we have identified a Tn5 mutant with an insertion in PA4130 showing reduced levels in a number of virulence traits in vitro. Construction of an isogenic mutant in this gene presented similar results as those from the Tn5 mutant. Furthermore, the PA4130 isogenic mutant showed substantial attenuation in disease models of Drosophila melanogaster, Caenorhabditis elegans as well as decreased toxicity in human cell lines. This mutant also presented an 80% increased survival in murine acute and agar-bead lung infection models. PA4130 codes for a protein with homology to nitrite and sulphite reductases. Overexpression of PA4130 in the presence of the siroheme synthase CysG enabled its purification as a soluble protein. Methyl viologen oxidation assays with purified PA4130 showed that this protein is a nitrite reductase operating in a siroheme and 4Fe-4S dependant manner. The preference for nitrite and the production of ammonium revealed that PA4130 is an ammonia:ferredoxin nitrite reductase and hence was named as NirA.

microbiology↗

bioRxiv2020

Pseudomonas aeruginosa biofilms display carbohydrate ligands for CD206 and CD209 that interfere with their receptor function

Bacterial biofilms represent a challenge to the healthcare system because of their resilience against antimicrobials and immune attack. Biofilms consist of bacterial aggregates embedded in an extracellular polymeric substance (EPS) composed of carbohydrate polymers, nucleic acids and proteins. Carbohydrates within P. aeruginosa biofilms include neutral and mannose-rich Psl, and cationic Pel composed of N-acetyl-galactosamine and N-acetyl-glucosamine. Here we show that P. aeruginosa biofilms display ligands for the C-type lectin receptors mannose receptor (MR, CD206) and Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN, CD209). Binding of MR and DC-SIGN to P. aeruginosa biofilms is carbohydrate-and calcium-dependent and extends to biofilms formed by clinical isolates. Confocal analysis of P. aeruginosa biofilms shows abundant DC-SIGN ligands among bacteria aggregates while MR ligands concentrate into discrete clusters. DC-SIGN ligands are also detected in planktonic P. aeruginosa cultures and depend on the presence of the common polysaccharide antigen. Carbohydrates purified from P. aeruginosa biofilms are recognised by DC-SIGN and MR; both receptors preferentially bind the high molecular weight fraction (HMW; >132,000Da) with KDs in the nM range. HMW preparations contain 74.9-80.9% mannose, display -mannan segments and alter the morphology of human dendritic cells without causing obvious changes in cytokine responses. Finally, HMW interferes with the endocytic activity of cell-associated MR and DC-SIGN. This work identifies MR and DC-SIGN as receptors for bacterial biofilms and highlights the potential for biofilm-associated carbohydrates as immunomodulators through engagement of C-type lectin receptors. Author SummarySelective engagement of pattern recognition receptors during infection guides the decision-making process during induction of immune responses. This work identifies mannose-rich carbohydrates within bacterial biofilms as novel molecular patterns associated with bacterial infections. P. aeruginosa biofilms and biofilm-derived carbohydrates bind two important lectin receptors, MR (CD206) and DC-SIGN (CD209), involved in recognition of self and immune evasion. Abundance of MR and DC-SIGN ligands in the context of P. aeruginosa biofilms could impact immune responses and promote chronic infection.

microbiology↗

bioRxiv2020

The analysis of the role of MexAB-OprM on quorum sensing homeostasis shows that the apparent redundancy of Pseudomonas aeruginosa multidrug efflux pumps allows keeping the robustness and the plasticity of this intercellular signaling network

Multidrug efflux pumps are key determinants for antibiotic resistance. Besides contributing to intrinsic resistance, their overexpression is frequently a cause of the increased resistance acquired during therapy. In addition to their role in resistance to antimicrobials, efflux pumps are ancient and conserved elements with relevant roles in different aspects of the bacterial physiology. It is then conceivable that their overexpression might cause a burden that will be translated into a fitness cost associated with the acquisition of resistance. In the case of Pseudomonas aeruginosa, it has been stated that overexpression of different efflux pumps is linked to the impairment of the quorum sensing (QS) response. Nevertheless, the causes of such impairment are different for each analyzed efflux pump. In this study, we performed an in-depth analysis of the QS-mediated response of a P. aeruginosa antibiotic resistant mutant that overexpresses MexAB-OprM. Although previous work claimed that this efflux pump extrudes the QS signal 3-oxo-C12-HSL, we show otherwise. Our results suggest that the observed attenuation in the QS response when overexpressing this pump is related to a reduced availability of intracellular octanoate, one of the precursors of the biosynthesis of alkyl quinolone QS signals. The overexpression of other P. aeruginosa efflux pumps has been shown to also cause a reduction in intracellular levels of QS signals or their precursors impacting on these signaling mechanisms. However, the molecules involved are distinct for each efflux pump, indicating that they can differentially contribute to the P. aeruginosa quorum sensing homeostasis. ImportanceThe success of bacterial pathogens to cause disease relies on their virulence capabilities as well as in their resistance to antibiotic interventions. In the case of the important nosocomial pathogen Pseudomonas aeruginosa, multidrug efflux pumps participate in the resistance/virulence crosstalk since, besides contributing to antibiotic resistance, they can also modulate the quorum sensing (QS) response. We show that mutants overexpressing the MexAB-OprM efflux pump, present an impaired QS response due to the reduced availability of the QS signal precursor octanoate, not because they extrude, as previously stated, the QS signal 3-oxo-C12-HSL. Together with previous studies, this indicates that, although the consequences of overexpressing efflux pumps are similar (impaired QS response), the mechanisms are different. This apparent redundancy of RND efflux systems can be understood as a P. aeruginosa strategy to keep the robustness of the QS regulatory network and modulate its output in response to different signals.

microbiology↗

bioRxiv2019

Cross-kingdom signalling regulates spore germination in the moss Physcomitrella patens

Plants live in close association with microorganisms that can have beneficial or detrimental effects. The activity of bacteria in association with flowering plants has been extensively analysed. Bacteria use quorum-sensing as a way of monitoring their population density and interacting with their environment. A key group of quorum sensing molecules in Gram-negative bacteria are the N-acylhomoserine lactones (AHLs), which are known to affect the growth and development of both flowering plants, including crops, and marine algae. Thus, AHLs have potentially important roles in agriculture and aquaculture. Nothing is known about the effects of AHLs on the earliest-diverging land plants, thus the evolution of AHL-mediated bacterial-plant- and algal interactions is unknown. In this paper, we show that AHLs can affect spore germination in a representative of the earliest plants on land, the Bryophyte moss Physcomitrella patens. Furthermore, we demonstrate that sporophytes of wild isolates of Physcomitrella patens are associated with AHL-producing bacteria.

plant biology↗

bioRxiv2018

The multidrug resistance efflux pump MexCD-OprJ is a switcher of the Pseudomonas aeruginosa quorum sensing response

Most antibiotic resistance genes acquired by human pathogens originate from environmental microorganisms. Therefore, understanding the additional functions of these genes, other than conferring antibiotic resistance, is relevant from an ecological point of view. We examined the effect that overexpression of the MexCD-OprJ multidrug efflux pump has in the physiology of the environmental opportunistic pathogen Pseudomonas aeruginosa. Overexpression of this intrinsic resistance determinant shuts down the P. aeruginosa quorum sensing (QS) response. Impaired QS response is due to the extrusion of 4-hydroxy-2-heptylquinoline (HHQ), the precursor of the Pseudomonas Quinolone Signal (PQS), leading to low PQS intracellular levels and reduced production of QS signal molecules. The P. aeruginosa QS response induces the expression of hundreds of genes, which can be costly unless such activation becomes beneficial for the bacterial population. While it is known that the QS response is modulated by population density, information on additional signals/cues that may alert the cells about the benefits of mounting the response is still scarce. It is possible that MexCD-OprJ plays a role in this particular aspect; our results indicate that, upon overexpression, MexCD-OprJ can act as a switcher in the QS population response. If MexCD-OprJ alleviate the cost associated to trigger the QS response when un-needed, it could be possible that MexCD-OprJ overproducer strains might be eventually selected even in the absence of antibiotic selective pressure, acting as antibiotic resistant cheaters in heterogeneous P. aeruginosa populations. This possibility may have potential implications for the treatment of P. aeruginosa chronic infections.

microbiology↗

bioRxiv2018

Ebola outbreak brings to light an unforeseen impact of tsetse control on sleeping sickness transmission in Guinea.

In addition to the thousands of deaths due the unprecedented ebola outbreak that stroke West Africa (2014-2016), national health systems in affected countries were deeply challenged impacting a number of diseases control programs. Here we describe the case of Human African Trypanosomiasis (HAT), a deadly neglected tropical disease due to a trypanosome transmitted by tsetse flies for which no vaccine nor chemoprophylaxis exists. Data are presented for the disease focus of Boffa in Guinea where a pilot elimination project combining medical screening and vector control was launched in 2012. During ebola, HAT active screening activities were postponed and passive surveillance also was progressively impaired. However, tsetse control using small insecticide impregnated targets could be maintained. The over two years disruption of screening activities led to a dramatic increase of HAT prevalence, from 0.7% in 2013 (21/2885) to 2% (69/3448) in 2016, reaching epidemic levels (>5%) in some villages. In deep contrast, control levels reached in 2013 (0.1%; 7/6564) were maintained in areas covered with impregnated targets as no cases were found in 2016 (0/799). In Boffa, ebola has thus incidentally provided a unique framework to assess the impact of current HAT control strategies. A first lesson is that the \"screen and treat\" strategy is fragile as rapid bursts of the disease may occur in case of disruption. A second lesson is that vector control reducing human-tsetse contacts, even implemented alone, is effective in providing a good level of protection against infection. This advocates for a greater attention being paid to the combination of tsetse control together with medical activities in aiming to reach the HAT elimination objective in Africa.

epidemiology↗

bioRxiv2017

T cell activation and the HLA locus associate with latent infections of human African trypanosomiasis

Infections by many pathogens can result in a wide range of phenotypes, from severe to mild, or even asymptomatic. Understanding the genetic basis of these phenotypes can lead to better tools to treat patients or detect reservoirs. To identify human genetic factors that contribute to symptoms diversity, we examined the range of disease severities caused by the parasite T. b. gambiense, the primary cause of human African trypanosomiasis (HAT). We analyzed the transcriptomes of immune cells from both symptomatic HAT cases and individuals with latent infections. Our analysis identified several genes and pathways that associated with the latent phenotype, primarily suggesting increased T and B cell activation in HAT patients relative to latent infections. We also used these transcriptome data to conduct an exome-wide single nucleotide polymorphism (SNP) association study. This suggested that SNPs in the human major histocompatibility locus (HLA) associate with severity, supporting the transcription data and suggesting that T cell activation is a determining factor in outcome. Finally, to establish if T cell activation controls disease severity, we blocked co-stimulatory dependent T cell activation in an animal model for HAT. This showed that reducing T cell activation during trypanosome infection improves symptoms and reduces parasitemia. Our data has used a combination of transcriptome-wide analysis and an in vivo model to reveal that T cell activation and the HLA locus associate with the development of symptoms during HAT. This may open new avenues for the development of new therapeutics and prognostics.

genetics↗