Publications

2022

Lafuse, William P, Qian Wu, Naresh Kumar, Noushin Saljoughian, Shrayes Sunkum, Omar Santiagonunez Ahumada, Joanne Turner, and Murugesan S Rajaram V. (2022) 2022. “Psychological Stress Creates an Immune Suppressive Environment in the Lung That Increases Susceptibility of Aged Mice to Mycobacterium Tuberculosis Infection.”. Frontiers in Cellular and Infection Microbiology 12: 990402. https://doi.org/10.3389/fcimb.2022.990402.

Age is a major risk factor for chronic infections, including tuberculosis (TB). Elderly TB patients also suffer from elevated levels of psychological stress. It is not clear how psychological stress impacts immune response to Mycobacterium tuberculosis (M.tb). In this study, we used social disruption stress (SDR) to investigate effects of psychological stress in young and old mice. Unexpectedly, we found that SDR suppresses lung inflammation in old mice as evidenced by lower pro-inflammatory cytokine levels in bronchial lavage fluid and decreased cytokine mRNA expression by alveolar macrophages. To investigate effects of stress on M.tb infection, mice were subjected to SDR and then infected with M.tb. As previously reported, old mice were better at controlling infection at 30 days than young mice. This control was transient as CFUs at 60 days were higher in old control mice compared to young mice. Consistently, SDR significantly increased M.tb growth at 60 days in old mice compared to young mice. In addition, SDR in old mice resulted in accumulation of IL-10 mRNA and decreased IFN-γ mRNA at 60 days. Also, confocal microscopy of lung sections from old SDR mice showed increased number of CD4 T cells which express LAG3 and CD49b, markers of IL-10 secreting regulatory T cells. Further, we also demonstrated that CD4 T cells from old SDR mice express IL-10. Thus, we conclude that psychological stress in old mice prior to infection, increases differentiation of IL-10 secreting T cells, which over time results in loss of control of the infection.

Olmo-Fontánez, Angélica M, and Joanne Turner. (2022) 2022. “Tuberculosis in an Aging World.”. Pathogens (Basel, Switzerland) 11 (10). https://doi.org/10.3390/pathogens11101101.

Tuberculosis (TB) is one of the leading causes of death due to its being an infectious disease, caused by the airborne pathogen Mycobacterium tuberculosis (M.tb). Approximately one-fourth of the world's population is infected with latent M.tb, and TB is considered a global threat killing over 4000 people every day. The risk of TB susceptibility and mortality is significantly increased in individuals aged 65 and older, confirming that the elderly represent one of the largest reservoirs for M.tb infection. The elderly population faces many challenges that increase their risk of developing respiratory diseases, including TB. The challenges the elderly face in this regard include the following: decreased lung function, immuno-senescence, inflammaging, adverse drug effects, low tolerance to anti-TB drugs, lack of suitable diagnoses/interventions, and age-associated comorbidities. In order to find new therapeutic strategies to maintain lung homeostasis and resistance to respiratory infections as we age, it is necessary to understand the molecular and cellular mechanisms behind natural lung aging. This review focuses primarily on why the elderly are more susceptible to TB disease and death, with a focus on pulmonary function and comorbidities.

Torrelles, J. B., B. I. Restrepo, Y. Bai, C. Ross, L. S. Schlesinger, and J. Turner. 2022. “The Impact of Aging on the Lung Alveolar Environment, Predetermining Susceptibility to Respiratory Infections”. Front Aging 3: 818700. https://doi.org/10.3389/fragi.2022.818700.
Respiratory infections are one of the top causes of death in the elderly population, displaying susceptibility factors with increasing age that are potentially amenable to interventions. We posit that with increasing age there are predictable tissue-specific changes that prevent the immune system from working effectively in the lung. This mini-review highlights recent evidence for altered local tissue environment factors as we age focusing on increased tissue oxidative stress with associated immune cell changes, likely driven by the byproducts of age-associated inflammatory disease. Potential intervention points are presented.
Scordo, J. M., T. J. Piergallini, A. M. Olmo-Fontanez, A. Thomas, H. P. Raue, M. Slifka, and J. Turner. 2022. “Recall Responses in the Lung Environment Are Impacted by Age in a Pilot Study of Mycobacterium Bovis-BCG Vaccinated Rhesus Macaques”. Exp Gerontol 167: 111904. https://doi.org/10.1016/j.exger.2022.111904.
Age-related changes in the immune system increase susceptibility to infectious diseases. Vaccines are an important tool to prevent infection or boost immunological memory; however, vaccines are less effective in aged individuals. In order to protect our aging population from the threat of infectious diseases, we must gain a better understanding of age-related alterations in the immune response at the site of infection. The lung is one site of frequent infection in older individuals. In this study, we expanded on our previous work to study vaccine-induced immune responses in the local lung environment in a pilot study of aged rhesus macaques. To do this, we developed an in vivo model to probe recall responses to tuberculin challenge in the lungs 8 weeks and 16 weeks post- Mycobacterium bovis BCG vaccination by performing targeted bronchoalveolar lavages. In parallel, we determined peripheral blood responses in vaccinated animals to compare systemic and local tissue responses to tuberculin challenge. We found that following lung tuberculin challenge 8 weeks post-vaccination, aged animals had reduced T cell responses, particularly within the CD8(+) T cell compartment. Aged animals had decreased CD8(+) effector and memory T cell recall responses and less activated CD8(+) T cells. This diminished lung CD8(+) T cell response in aged animals was maintained over time. Despite changes in the CD8(+) T cell compartment, lung CD4(+) T cell responses were similar between age groups. In the peripheral blood, we observed age-related changes in immune cell populations and plasma levels of immune mediators that were present prior to vaccination. Lastly, we found that peripheral blood mononuclear cells from aged BCG-vaccinated animals were functional in their response to antigen stimulation, behaving in a similar manner to those from their adult counterparts. These systemic observations were similar to those found in our previous study of BCG-vaccinated baboons, supporting the notion that tissue immune responses, and not systemic responses, to vaccination and challenge are impaired with age. These findings expand on our previous work to show that in addition to the skin, age-related changes in the lung environment impact recall immune responses to vaccination and challenge. The impact of age on local tissue responses to infectious challenge should be accounted for in the development of therapeutics or medical interventions aimed at boosting immune recall responses of aged individuals.
Dwivedi, V., S. Gautam, C. A. Headley, T. Piergallini, J. B. Torrelles, and J. Turner. 2022. “IL-10 Receptor Blockade Delivered Simultaneously With Bacillus Calmette- Guerin Vaccination Sustains Long-Term Protection Against Mycobacterium Tuberculosis Infection in Mice”. J Immunol 208: 1406-16. https://doi.org/10.4049/jimmunol.2100900.
Mycobacterium bovis bacillus Calmette-Guerin (BCG) immunization still remains the best vaccination strategy available to control the development of active tuberculosis. Protection afforded by BCG vaccination gradually wanes over time and although booster strategies have promise, they remain under development. An alternative approach is to improve BCG efficacy through host-directed therapy. Building upon prior knowledge that blockade of IL-10R1 during early Mycobacterium tuberculosis infection improves and extends control of M. tuberculosis infection in mice, we employed a combined anti-IL-10R1/BCG vaccine strategy. An s.c. single vaccination of BCG/anti-IL10-R1 increased the numbers of CD4(+) and CD8(+) central memory T cells and reduced Th1 and Th17 cytokine levels in the lung for up to 7 wk postvaccination. Subsequent M. tuberculosis challenge in mice showed both an early (4 wk) and sustained long-term (47 wk) control of infection, which was associated with increased survival. In contrast, protection of BCG/saline-vaccinated mice waned 8 wk after M. tuberculosis infection. Our findings demonstrate that a single and simultaneous vaccination with BCG/anti-IL10-R1 sustains long-term protection, identifying a promising approach to enhance and extend the current BCG-mediated protection against TB.
Restrepo, B. I., J. M. Scordo, G. P. Aguillon-Duran, D. Ayala, A. P. Quirino-Cerrillo, R. Loera-Salazar, A. Cruz-Gonzalez, et al. 2022. “Differential Role of Type 2 Diabetes As a Risk Factor for Tuberculosis in the Elderly versus Younger Adults”. Pathogens 11. https://doi.org/10.3390/pathogens11121551.
The elderly are understudied despite their high risk of tuberculosis (TB). We sought to identify factors underlying the lack of an association between TB and type 2 diabetes (T2D) in the elderly, but not adults. We conducted a case-control study in elderly (>/=65 years old; ELD) vs. younger adults (young/middle-aged adults (18-44/45-64 years old; YA|MAA) stratified by TB and T2D, using a research study population (n = 1160) and TB surveillance data (n = 8783). In the research study population the adjusted odds ratio (AOR) of TB in T2D was highest in young adults (AOR 6.48) but waned with age becoming non-significant in the elderly. Findings were validated using TB surveillance data. T2D in the elderly (vs. T2D in younger individuals) was characterized by better glucose control (e.g., lower hyperglycemia or HbA1c), lower insulin resistance, more sulphonylureas use, and features of less inflammation (e.g., lower obesity, neutrophils, platelets, anti-inflammatory use). We posit that differences underlying glucose dysregulation and inflammation in elderly vs. younger adults with T2D, contribute to their differential association with TB. Studies in the elderly provide valuable insights into TB-T2D pathogenesis, e.g., here we identified insulin resistance as a novel candidate mechanism by which T2D may increase active TB risk.

2021

PrabhuDas, Mercy, Rebecca Fuldner, Donna Farber, George A Kuchel, Joan Mannick, Janko Nikolich-Zugich, Ranjan Sen, and Joanne Turner. (2021) 2021. “Research and Resource Needs for Understanding Host Immune Responses to SARS-CoV-2 and COVID-19 Vaccines During Aging.”. Nature Aging 1 (12): 1073-77. https://doi.org/10.1038/s43587-021-00156-x.

On 16 and 17 March 2021, the National Institute of Allergy and Infectious Diseases and the National Institute of Aging convened a virtual workshop to discuss developments in SARS-CoV-2 research pertaining to immune responses in older adults, COVID-19 vaccines in both aged animals and older individuals, and to gain some perspective on the critical knowledge gaps that need addressing to establish scientific priorities for future research studies.

Singh, Dhiraj Kumar, Bindu Singh, Shashank R Ganatra, Michal Gazi, Journey Cole, Rajesh Thippeshappa, Kendra J Alfson, et al. (2021) 2021. “Responses to Acute Infection With SARS-CoV-2 in the Lungs of Rhesus Macaques, Baboons and Marmosets.”. Nature Microbiology 6 (1): 73-86. https://doi.org/10.1038/s41564-020-00841-4.

Non-human primate models will expedite therapeutics and vaccines for coronavirus disease 2019 (COVID-19) to clinical trials. Here, we compare acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in young and old rhesus macaques, baboons and old marmosets. Macaques had clinical signs of viral infection, mild to moderate pneumonitis and extra-pulmonary pathologies, and both age groups recovered in two weeks. Baboons had prolonged viral RNA shedding and substantially more lung inflammation compared with macaques. Inflammation in bronchoalveolar lavage was increased in old versus young baboons. Using techniques including computed tomography imaging, immunophenotyping, and alveolar/peripheral cytokine response and immunohistochemical analyses, we delineated cellular immune responses to SARS-CoV-2 infection in macaque and baboon lungs, including innate and adaptive immune cells and a prominent type-I interferon response. Macaques developed T-cell memory phenotypes/responses and bystander cytokine production. Old macaques had lower titres of SARS-CoV-2-specific IgG antibody levels compared with young macaques. Acute respiratory distress in macaques and baboons recapitulates the progression of COVID-19 in humans, making them suitable as models to test vaccines and therapies.

Metelmann, Soeren, Karan Pattni, Liam Brierley, Lisa Cavalerie, Cyril Caminade, Marcus S C Blagrove, Joanne Turner, Kieran J Sharkey, and Matthew Baylis. (2021) 2021. “Impact of Climatic, Demographic and Disease Control Factors on the Transmission Dynamics of COVID-19 in Large Cities Worldwide.”. One Health (Amsterdam, Netherlands) 12: 100221. https://doi.org/10.1016/j.onehlt.2021.100221.

Approximately a year into the COVID-19 pandemic caused by the SARS-CoV-2 virus, many countries have seen additional "waves" of infections, especially in the temperate northern hemisphere. Other vulnerable regions, such as South Africa and several parts of South America have also seen cases rise, further impacting local economies and livelihoods. Despite substantial research efforts to date, it remains unresolved as to whether COVID-19 transmission has the same sensitivity to climate observed for other common respiratory viruses such as seasonal influenza. Here, we look for empirical evidence of seasonality using a robust estimation framework. For 359 large cities across the world, we estimated the basic reproduction number (R0) using logistic growth curves fitted to cumulative case data. We then assess evidence for association with climatic variables through ordinary least squares (OLS) regression. We find evidence of seasonality, with lower R0 within cities experiencing greater surface radiation (coefficient = -0.005, p < 0.001), after adjusting for city-level variation in demographic and disease control factors. Additionally, we find association between R0 and temperature during the early phase of the epidemic in China. However, climatic variables had much weaker explanatory power compared to socioeconomic and disease control factors. Rates of transmission and health burden of the continuing pandemic will be ultimately determined by population factors and disease control policies.

Aguillón-Durán, Génesis P, Ericka Prieto-Martínez, Doris Ayala, Juan García, John M Thomas, Juan Ignacio García, Brandon Michael Henry, et al. (2021) 2021. “COVID-19 and Chronic Diabetes: the Perfect Storm for Reactivation Tuberculosis?: A Case Series.”. Journal of Medical Case Reports 15 (1): 621. https://doi.org/10.1186/s13256-021-03193-7.

BACKGROUND: The coronavirus disease 2019 pandemic is predicted to have a net negative effect on tuberculosis control, with an estimated excess of 6.3 million tuberculosis cases and 1.4 million deaths by 2025. Programmatic issues such as the lockdown of tuberculosis services affect all patients, while biosocial factors have a differential impact on an individual's risk for tuberculosis or adverse tuberculosis outcomes.

CASE PRESENTATION: We report three Hispanic cases of incident tuberculosis (two males, 43 and 44 years old; one female, 49 years old) after resolution of coronavirus disease episodes. Coincidentally, all cases shared a common risk factor: a chronic history poorly controlled diabetes.

CONCLUSIONS: Our findings alert to the threat posed by the synergy between coronavirus disease and diabetes, on tuberculosis reactivation. In medium- to high-risk settings for tuberculosis, we recommend implementation of routine screening for latent tuberculosis infection in these cases, and preventive tuberculosis treatment in those who are positive.