Immune Phenotype and Functionality of Mtb-Specific T-Cells in HIV/TB Co-Infected Patients on Antiretroviral Treatment

Mupfumi, Lucy; Mpande, Cheleka A M; Reid, Tim; Moyo, Sikhulile; Shin, Sanghyuk S.; Zetola, Nicola M.; Mogashoa, Tuelo; Musonda, Rosemary; Kasvosve, Ishmael; Scriba, Thomas J.; Nemes, Elisa; Gaseitsiwe, Simani

doi:10.3390/pathogens9030180

Cited by 6 publications

(4 citation statements)

References 33 publications

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“…Immune responses influence the outcome of any disease, and an increased number of CD16 + and NK cells in the HHCs is associated with LTBI (41). In TB endemic countries, NK cell phenotypes and functional profiles are modified, and these immune phenotypes can be used for the diagnosis of TB (42)(43)(44). We found significantly higher numbers of CD16-expressing CD14 + cells and CCR7-expressing CD3 -CD56 + CD27 + memory-like NK cells in nonconverters than in converters at baseline (Figure 1B), suggesting that the immune cell phenotype can play a role in resistance to TB in nonconverters.…”

Section: Discussionmentioning

confidence: 99%

Metabolites enhance innate resistance to human Mycobacterium tuberculosis infection

Tripathi¹,

Devalraju²,

Neela³

et al. 2022

JCI Insight

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We characterized the phenotype and function of various immune cells in a large group of LTBI -HHCs (nonconverters) of patients with TB (a total of 452 individuals). We performed these measures at baseline (0 months) and follow-up (24 months) while monitoring the participants for conversion to LTBI. By following a large cohort of HHCs of patients with TB and performing transcriptional and metabolomic studies, we determined whether resistance to M. tuberculosis infection is preceded by specific changes in the transcriptional profile. We also determined whether metabolites regulate macrophage metabolism and function to restrict M. tuberculosis growth. ResultsPrevalence of nonconverters in the HHCs of patients with TB. At baseline, among 990 HHCs, 538 (54.3%) were positive and 452 (45.6%) were negative for LTBI by the IFN-γ release assay (IGRA) as described in the Methods (Supplemental Table 1; supplemental material available online with this article; https://doi.org/10.1172/ jci.insight.152357DS1). We followed these 452 LTBI -HHCs for 2 years at 4-month intervals (study plan is shown in Figure 1A). Exposure to index patients was determined following the criteria mentioned in previous studies (10-14) and in the Methods section. Among the 452 LTBI -HHCs, 96 (21.2%) became IGRA + (converters) over 2 years of follow-up. Despite similar exposure levels, 293 (64.8%) HHCs remained IGRA -(nonconverters) until the end of the study (Table 1 and Supplemental Data 1). As shown in Supplemental Data 1, all (n = 96) converters consistently produced IFN-γ in response to M. tuberculosis antigens. The demographic details of converters and nonconverters are shown in Table 1 and Supplemental Table 1.Immune cell phenotypes of converters and nonconverters. The innate immune response is critical to clear M. tuberculosis infection and may play an important role in preventing LTBI conversion (15-18). We determined various immune cell populations at baseline and during the follow-up visits (24 months) in freshly isolated peripheral blood mononuclear cells (PBMCs) of age-and sex-matched nonconverters (n = 293) and converters (n = 96). At baseline, in fresh PBMCs of nonconverters, the percentages of CD14 + and CD3 -CD56 + CD27 + CCR7 + memory-like NK cells were significantly higher than those of converters (Figure 1B and Supplemental Figure 1). No significant differences in CD4 + , CD16 + , CD14 + CD16 + , CD16 + CD56 + , or CD4 + CD25 + FoxP3 + cells were found in the PBMCs of nonconverters and converters (Figure 1B). As shown in Figure 1B, the percentage of memory-like NK cells significantly decreased in converters at follow-up. However, in nonconverters, the percentages of the cells remained the same throughout the study (Figure 1B).Cytokine and chemokine production by the PBMCs of converters and nonconverters in response to M. tuberculosis antigens. Various cytokines and chemokines produced following M. tuberculosis exposure are crucial to the outcome of infection (19,20). We determined cytokine and chemokine production by PBMCs of convert...

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Section: Discussionmentioning

confidence: 99%

Metabolites enhance innate resistance to human Mycobacterium tuberculosis infection

Tripathi¹,

Devalraju²,

Neela³

et al. 2022

JCI Insight

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“…In HIV-infected patients presenting with advanced immunodeficiency, assessment of TB-specific T-cell responses may be compromised. However, it has been demonstrated that CD38, HLA-DR and Ki-67 are appropriate markers for the discrimination of TB infection and TB disease in HIV-infected TB patients with moderate immunodeficiency [12,31]. Future investigations need to include cohorts of patients with HIV infection and advanced immunodeficiency as well as otherwise immunosuppressed patients.…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis-specific CD4 T-cell scoring discriminates tuberculosis infection from disease

Mantei

Meyer²,

Schürmann³

et al. 2022

Eur Respir J

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Rapid and reliable diagnostic work-up of tuberculosis (TB) remains a major healthcare goal. In particular, discrimination of TB infection from TB disease with currently available diagnostic tools is challenging and time-consuming. This study aimed at establishing a standardised blood-based assay that rapidly and reliably discriminates TB infection from disease based on multiparameter analysis of TB antigen-reactive CD4+ T cells acting as sensors for the TB stage-specific immune status.A total of 157 HIV-negative subjects suspected with TB infection or disease was recruited from local tertiary care hospitals. Peripheral blood mononuclear cells were analysed for CD4+ T cells reactive to the Mycobacterium tuberculosis antigens PPD and ESAT-6/CFP-10. The activation state of TB antigen-reactive T cells, identified by surface expression of CD154, was evaluated according to the expression profile of proliferation marker Ki-67 and activation markers CD38 and HLA-DR. Using data from 81 subjects with clinically confirmed TB infection (n=34) or culture-proven pulmonary or extrapulmonary TB disease (n=47) twelve parameters were derived from the expression profile and integrated into a scoring system.Using the scoring system our assay allowed reliable discrimination of TB infection from both pulmonary and extrapulmonary TB disease with high sensitivity (90.9%) and specificity (93.3%) as was confirmed by Monte-Carlo cross validation.With low time requirement, ease of sample collection and high sensitivity and specificity both for pulmonary and extrapulmonary TB disease, we believe this novel standardised TB-Flow Assay will improve the work-up of patients with suspected TB disease supporting rapid TB diagnosis and facilitating treatment decisions.

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“…Assessing the activation of M.tb-specific T cells is an active field to develop TB immunodiagnosis, for example looking at CD4 + IFN-g + T cells for HLA-DR, CD38, and Ki-67 markers, which shows 100% sensitivity and 95% specificity for active TB (86)(87)(88). Phenotypic changes on M.tb-specific CD4 T cells are also used as surrogate markers for TB treatment efficacy and can help to discriminate between TB (profile: CD38 pos , CD27 low ), treated TB (CD38 neg , CD27 low ), and LTBI (CD38 neg , CD27 high ) (89).…”

Section: Immunodiagnostics Of Latent Mtb Infection (Ltbi)mentioning

confidence: 99%

Tuberculosis Phenotypic and Genotypic Drug Susceptibility Testing and Immunodiagnostics: A Review

Yusoof

García²,

Schami³

et al. 2022

Front. Immunol.

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Tuberculosis (TB), considered an ancient disease, is still killing one person every 21 seconds. Diagnosis of Mycobacterium tuberculosis (M.tb) still has many challenges, especially in low and middle-income countries with high burden disease rates. Over the last two decades, the amount of drug-resistant (DR)-TB cases has been increasing, from mono-resistant (mainly for isoniazid or rifampicin resistance) to extremely drug resistant TB. DR-TB is problematic to diagnose and treat, and thus, needs more resources to manage it. Together with+ TB clinical symptoms, phenotypic and genotypic diagnosis of TB includes a series of tests that can be used on different specimens to determine if a person has TB, as well as if the M.tb strain+ causing the disease is drug susceptible or resistant. Here, we review and discuss advantages and disadvantages of phenotypic vs. genotypic drug susceptibility testing for DR-TB, advances in TB immunodiagnostics, and propose a call to improve deployable and low-cost TB diagnostic tests to control the DR-TB burden, especially in light of the increase of the global burden of bacterial antimicrobial resistance, and the potentially long term impact of the coronavirus disease 2019 (COVID-19) disruption on TB programs.

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Immune Phenotype and Functionality of Mtb-Specific T-Cells in HIV/TB Co-Infected Patients on Antiretroviral Treatment

Cited by 6 publications

References 33 publications

Metabolites enhance innate resistance to human Mycobacterium tuberculosis infection

Metabolites enhance innate resistance to human Mycobacterium tuberculosis infection

Mycobacterium tuberculosis-specific CD4 T-cell scoring discriminates tuberculosis infection from disease

Tuberculosis Phenotypic and Genotypic Drug Susceptibility Testing and Immunodiagnostics: A Review

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