A Novel Humanized Mouse Model for HIV and Tuberculosis Co-infection Studies
José Alejandro BohórquezSitaramaraju AdduriDanish AnsariSahana JohnJon FlorenceOmoyeni AdejareGaurav SinghNagarjun V. KonduruChinnaswamy JagannathGuohua Yi
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ABSTRACT Tuberculosis (TB), caused by Mycobacterium tuberculosis ( Mtb ), continues to be a major public health problem worldwide. The human immunodeficiency virus (HIV) is another equally important life-threatening pathogen. Further, co-infections with HIV and Mtb have severe effects in the host, with people infected with HIV being fifteen to twenty-one times more likely to develop active TB. The use of an appropriate animal model for HIV/ Mtb co-infection that can recapitulate the diversity of the immune response in humans would be a useful tool for conducting basic and translational research in HIV/ Mtb infections. The present study was focused on developing a humanized mouse model for investigations on HIV- Mtb co-infection. Using NSG-SGM3 mice that can engraft human stem cells, our studies showed that they were able to engraft human CD34+ stem cells which then differentiate into a full-lineage of human immune cell subsets. After co-infection with HIV and Mtb , these mice showed decrease in CD4+ T cell counts overtime and elevated HIV load in the sera, similar to the infection pattern of humans. Additionally, Mtb caused infections in both lungs and spleen, and induced the development of granulomatous lesions in the lungs, detected by CT scan and histopathology. Distinct metabolomic profiles were also observed in the tissues from different mouse groups after co-infections. Our results suggest that the humanized NSG-SGM3 mice are able to recapitulate the effects of HIV and Mtb infections and co-infection in the human host at pathological, immunological and metabolism levels, providing a dependable small animal model for studying HIV/ Mtb co-infection.Keywords:
Humanized mouse
In 2015, tuberculosis ranked as the leading cause of
death from an infectious disease, surpassing HIV/AIDS.(1)
In 2016, an estimated 10.4 million people developed
tuberculosis and 1.7 million died from the disease, 5,000
people dying from it every day, including approximately
1,000 individuals with tuberculosis/HIV coinfection.(1) In
the past decade, the global tuberculosis community has
engaged in activities to successfully attain the Millennium
Development Goal target and other international targets
for halting and reversing increases in tuberculosis incidence
and mortality.(1) However, despite the achievements
made to date, the global incidence of tuberculosis is
declining at a rate of only 1.5% per year, far from the
10% expected.
History of tuberculosis
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Multidrug-resistant (MDR) tuberculosis has increased among migrants in Canada. The cause(s) of this increase is unknown.We performed a retrospective cohort study in a Canadian province with substantially increased immigration between 1982-2001 and 2002-2019. The proportion of MDR tuberculosis among migrants arriving from high MDR (HMDR) tuberculosis burden countries during these 2 periods was used to estimate the proportion of cases due to immigration versus change in proportion in the country of birth. Epidemiologic, spatiotemporal, and drug resistance pattern data were used to confirm local transmission.Fifty-two of 3514 (1.48%) foreign-born culture-positive tuberculosis patients had MDR tuberculosis: 8 (0.6%) in 1982-2001 and 44 (2.0%) in 2002-2019. Between time periods, the proportion of MDR tuberculosis among migrants with tuberculosis from HMDR tuberculosis countries increased from 1.11% to 3.62%, P = .003; 31.6% attributable to recent immigration and 68.4% to a higher proportion of MDR tuberculosis in cases arrived from HMDR tuberculosis countries. No cases of MDR tuberculosis were attributable to local transmission.In stark contrast to HMDR tuberculosis countries, local transmission plays no important role in the occurrence of MDR tuberculosis in Canada. Improved tuberculosis programming in HMDR tuberculosis countries is urgently needed.
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Primary Mycobacterium tuberculosis transmission is an important driver of the global epidemic of resistance to tuberculosis drugs. A few studies have compared tuberculosis infection in contacts of index cases with different drug-resistant profiles, suggesting that contacts of multidrug-resistant (MDR) tuberculosis cases are at higher risk. Repeated tuberculosis exposure in contacts of MDR tuberculosis patients through recurrent tuberculosis may modify this relationship. We compared tuberculosis infection in household contacts of MDR and drug-susceptible (DS) tuberculosis patients from six cities in southeastern China and investigated whether repeated tuberculosis exposure was a mediating factor. Tuberculosis infection was defined as a tuberculin skin test induration ≥ 10 mm. In all, 111 (28.0%) of 397 household contacts of MDR tuberculosis patients and 165 (24.7%) of 667 contacts of DS tuberculosis index cases were infected with tuberculosis. In a multivariate model not including the previous tuberculosis exposure, contacts of MDR tuberculosis patients had a higher likelihood of tuberculosis infection (adjusted odds ratio [AOR] = 1.37; 95% confidence interval [CI] = 1.01-1.84; P = 0.041). In a separate multivariate model adjusted for the previous tuberculosis exposure, the odds ratio of tuberculosis infection flipped and contacts of MDR cases were now at lower risk for tuberculosis infection (AOR = 0.55; 95% CI = 0.38-0.81; P = 0.003). These findings suggest prior tuberculosis exposure in contacts strongly mediates the relationship between tuberculosis infection and the index drug resistance profile. Prior studies showing lower risk of developing tuberculosis among contacts of MDR tuberculosis patients may be partially explained by a lower rate of tuberculosis infection at baseline.
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Tuberculosis is now the leading cause of death due an infectious disease.1WHOGlobal Tuberculosis Report 2017. World Health Organization, Geneva2017Google Scholar Urgent action with new approaches is needed to achieve WHO's elimination targets of an 80% reduction in tuberculosis cases and a 90% reduction in deaths by 2030.1WHOGlobal Tuberculosis Report 2017. World Health Organization, Geneva2017Google Scholar Marx and colleagues2Marx FM Floyd S Ayles H Godfrey-Faussett P Beyers N Cohen T High burden of prevalent tuberculosis among previously treated people in Southern Africa suggests potential for targeted control interventions.Eur Respir J. 2016; 48: 1227-1230Crossref PubMed Scopus (27) Google Scholar previously identified that, in high tuberculosis burden communities in sub-Saharan Africa, individuals who have previously been treated for tuberculosis have as much as a 5 times increased risk of a repeat tuberculosis disease episode compared with individuals without a history of tuberculosis treatment. Furthermore, the investigators noted that previous tuberculosis treatment was reported in 18·5% of prevalent tuberculosis cases. These findings were restricted to HIV-uninfected adults; the difference in risk based on previous tuberculosis episode was not significant in individuals with HIV. These findings suggest that HIV-uninfected individuals previously treated for tuberculosis are a potential focus for a targeted approach in tuberculosis disease prevention. In The Lancet Global Health, Florian Marx and colleagues3Marx FM Yaesoubi R Menzies NA et al.Tuberculosis control interventions targeted to previously treated people in a high-incidence setting: a modelling study.Lancet Glob Health. 2018; (published online Feb 19.)http://dx.doi.org/10.1016/S2214-109X(18)30022-6Summary Full Text Full Text PDF PubMed Scopus (28) Google Scholar investigate the effect of two control strategies directed at previously treated individuals in a suburb of Cape Town, South Africa—a setting with high tuberculosis recurrence rates and low HIV co-prevalence. The team modelled two interventions: active case finding among previously treated cases alone and the active case finding paired with life-long isoniazid preventive therapy following treatment completion of the initial tuberculosis episode. The researchers found that combining these two interventions could achieve a 40% reduction in incidence and a 41% reduction in tuberculosis deaths over 10 years. The benefit of such targeted interventions can be separated into two components: avoiding recurrence and improving early identification of tuberculosis disease in previously treated individuals (which contributes to a roughly 30% reduction in incidence) and preventing new infections attributable to transmission from those cases (which contributes a further 10% reduction in incidence). Predicting the effect of targeted interventions in other settings using a modelling approach requires detailed knowledge of local transmission and epidemiology. The investigators showed that, with similar assumptions and a force of infection cut in half, targeting previously treated cases can avert a third of incident disease. For other settings, an estimate of the direct effect can be calculated using the proportion of recurrent tuberculosis cases, often measured using molecular epidemiological data.4Uys PW van Helden PD Hargrove JW Tuberculosis reinfection rate as a proportion of total infection rate correlates with the logarithm of the incidence rate: a mathematical model.J R Soc Interface. 2009; 6: 11-15Crossref PubMed Scopus (41) Google Scholar The indirect effect can be estimated using the fraction of recurrent cases combined with their relative risk of transmission.5Brooks-Pollock E Danon L Defining the population attributable fraction for infectious diseases.Int J Epidemiol. 2017; 46: 976-982Crossref PubMed Scopus (13) Google Scholar Here, for example, previously treated cases were assumed to be 1·5 times more likely to transmit tuberculosis than treatment-naive cases. The population-level effects of targeting previously treated cases are compelling. As Marx and colleagues outline, this is a group of individuals who have engaged with the medical system and can be traced through those services. However, several individual-level issues should be considered. First, the reason that previously treated tuberculosis cases contribute such a high proportion of incident disease could lead to modification of the intervention. If inherent host factors drive the increased susceptibility to disease progression, then lifelong prophylaxis might be reasonable to protect them. However, if increased risk is due to immunological defects that improve over time, a more time-limited prophylaxis is more appropriate.6Uys P Brand H Warren R van der Spuy G Hoal EG van Helden PD The risk of tuberculosis reinfection soon after cure of a first disease episode is extremely high in a hyperendemic community.PLoS One. 2015; 10: e0144487Crossref PubMed Scopus (15) Google Scholar Second, recognition that isoniazid is not easily tolerated over long periods because of liver toxicity is important.7Saukkonen JJ Cohn DL Jasmer RM et al.An official ATS statement: hepatotoxicity of antituberculosis therapy.Am J Respir Crit Care Med. 2006; 174: 935-952Crossref PubMed Scopus (843) Google Scholar Individuals are instructed to avoid acetaminophen and alcohol while on isoniazid; to ask for such lifelong modifications would benefit from quantifying an individual-level benefit in addition to that for the community. Finally, the anticipation of being able to capture 90% of the previously treated population and maintain them on isoniazid therapy for a median of 6 years is optimistic. Others have reported that patients with tuberculosis are often quite mobile, especially after completing care, and that even during care, dropout rates are high (conservatively 9% in the Western Cape Province from which the model cohort resides).8Dudley L Mukinda F Dyers R Marais F Sissolak D Mind the gap! Risk factors for poor continuity of care of tuberculosis patients discharged from a hospital in the Western Cape, South Africa.PLoS One. 2018; 13: e0190258Crossref PubMed Scopus (12) Google Scholar Implementation of isoniazid preventive care for individuals with HIV has had variable uptake.9Akolo C Bada F Okpokoro E et al.Debunking the myths perpetuating low implementation of isoniazid preventive therapy amongst human immunodeficiency virus-infected persons.World J Virol. 2015; 4: 105-112Crossref PubMed Google Scholar Additionally, the stigma of having had a tuberculosis diagnosis is prevalent, so consideration of tagging a group of individuals over a long period with having this diagnosis might not be desirable without addressing such stigma as well.10Daftary A Frick M Venkatesan N Pai M Fighting tuberculosis stigma: we need to apply lessons learnt from HIV activism.BMJ Glob Health. 2017; 2: e000515Crossref PubMed Scopus (44) Google Scholar We are encouraged by the modelling of this novel approach by Marx and colleagues ahead of consideration of how to successfully develop an intervention study. For real progress to be made in tuberculosis control, innovative-targeted approaches will be necessary to successfully reduce disease rates, balancing individual and community level benefits. We declare no competing interests. Tuberculosis control interventions targeted to previously treated people in a high-incidence setting: a modelling studyIn this high-incidence setting, the use of targeted active case finding in combination with secondary isoniazid preventive therapy in previously treated individuals could accelerate decreases in tuberculosis morbidity and mortality. Studies to measure cost and resource implications are needed to establish the feasibility of this type of targeted approach for improving tuberculosis control in settings with high tuberculosis and HIV prevalence. Full-Text PDF Open Access
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The effectiveness of the Diaskintest for detecting tuberculosis in 61 children and young people in the Children's Hospital of Samara city was studied. The most frequent forms of tuberculosis were intrathoracic lymph node tuberculosis (39, 3%) and infiltrative tuberculosis (27,9%).
The Diaskintest® has shown its high diagnostic importance when dealing with local forms of active tuberculosis (88,5%). The negative test result by Diaskintest® does not exclude presence of tuberculosis. The Mantoux test remains important diagnostic test for detecting tuberculosis.
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The risk and timing of tuberculosis among recently exposed close contacts of patients with infectious tuberculosis are not well established.
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Tuberculosis remains a global health problem with an enormous burden of disease, estimated at 10.4 million new cases in 2015. To stop the tuberculosis epidemic, it is critical that we interrupt tuberculosis transmission. Further, the interventions required to interrupt tuberculosis transmission must be targeted to high-risk groups and settings. A simple cascade for tuberculosis transmission has been proposed in which (1) a source case of tuberculosis (2) generates infectious particles (3) that survive in the air and (4) are inhaled by a susceptible individual (5) who may become infected and (6) then has the potential to develop tuberculosis. Interventions that target these events will interrupt tuberculosis transmission and accelerate the decline in tuberculosis incidence and mortality. The purpose of this article is to provide a high-level overview of what is known about tuberculosis transmission, using the tuberculosis transmission cascade as a framework, and to set the scene for the articles in this series, which address specific aspects of tuberculosis transmission.
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History of tuberculosis
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The number of humanized mouse models for the human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) and other infectious diseases has expanded rapidly over the past 8 years. Highly immunodeficient mouse strains, such as NOD/SCID/gamma chain(null) (NSG, NOG), support better human hematopoietic cell engraftment. Another improvement is the derivation of highly immunodeficient mice, transgenic with human leukocyte antigens (HLAs) and cytokines that supported development of HLA-restricted human T cells and heightened human myeloid cell engraftment. Humanized mice are also used to study the HIV reservoir using new imaging techniques. Despite these advances, there are still limitations in HIV immune responses and deficits in lymphoid structures in these models in addition to xenogeneic graft-versus-host responses. To understand and disseminate the improvements and limitations of humanized mouse models to the scientific community, the NIH sponsored and convened a meeting on April 15, 2015 to discuss the state of knowledge concerning these questions and best practices for selecting a humanized mouse model for a particular scientific investigation. This report summarizes the findings of the NIH meeting.
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There is considerable variability in the outcome of Mycobacterium tuberculosis infection. We hypothesized that Mycobacterium africanum was less likely than M. tuberculosis to transmit and progress to tuberculosis disease.In a cohort study of patients with tuberculosis and their household contacts in The Gambia, we categorized 1808 HIV-negative tuberculosis contacts according to exposure to M. tuberculosis or M. africanum. Positive skin test results indicated transmission, and development of tuberculosis during 2 years of follow-up indicated progression to disease.Transmission rates were similar, but rates of progression to disease were significantly lower in contacts exposed to M. africanum than in those exposed to M. tuberculosis (1.0% vs. 2.9%; hazard ratio [HR], 3.1 [95% confidence interval {CI}, 1.1-8.7]). Within M. tuberculosis sensu stricto, contacts exposed to a Beijing family strain were most likely to progress to disease (5.6%; HR relative to M. africanum, 6.7 [95% CI, 2.0-22]).M. africanum and M. tuberculosis transmit equally well to household contacts, but contacts exposed to M. africanum are less likely to progress to tuberculosis disease than those exposed to M. tuberculosis. The variable rate of progression by lineage suggests that tuberculosis variability matters in clinical settings and should be accounted for in studies evaluating tuberculosis vaccines and treatment regimens for latent tuberculosis infection.
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