Publications

2021

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.
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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.

Scordo, J. M., T. J. Piergallini, N. Reuter, C. A. Headley, V. L. Hodara, O. Gonzalez, L. D. Giavedoni, J. F. Papin, and J. Turner. 2021. “Local Immune Responses to Tuberculin Skin Challenge in Mycobacterium Bovis BCG-Vaccinated Baboons: A Pilot Study of Younger and Older Animals”. Immun Ageing 18: 16. https://doi.org/10.1186/s12979-021-00229-w.
Individuals over the age of 65 are highly susceptible to infectious diseases, which account for one-third of deaths in this age group. Vaccines are a primary tool to combat infection, yet they are less effective in the elderly population. While many groups have aimed to address this problem by studying vaccine-induced peripheral blood responses in the elderly, work from our lab and others demonstrate that immune responses to vaccination and infectious challenge may differ between tissue sites and the periphery. In this pilot study, we established an in vivo delayed-type hypersensitivity model of Mycobacterium bovis BCG vaccination and tuberculin skin test in two adult and two aged baboons. Vaccination generates BCG-specific immune cells that are recruited to the skin upon tuberculin challenge. We tested short term recall responses (8 weeks post-vaccination) and long term recall responses (25 weeks post-vaccination) by performing skin punch biopsies around the site of tuberculin injection. In short term recall responses, we found increased oxidation and decreased production of immune proteins in aged baboon skin at the site of TST challenge, in comparison to adult skin. Differences between adult and aged animals normalized in the long term response to tuberculin. In vitro, aged peripheral blood mononuclear cells had increased migration and functional responses to antigen- specific stimulation, suggesting that age-related changes in the tissue in vivo impairs aged immune recall responses to antigenic challenge. These findings highlight the impact of age-associated changes in the local tissue environment in memory recall responses, which may be more broadly applied to the study of other tissues. Moreover, these findings should be considered in future studies aimed at understanding and improving aging immune responses to vaccination and tissue challenge.
Scordo, J. M., G. P. Aguillon-Duran, D. Ayala, A. P. Quirino-Cerrillo, E. Rodriguez-Reyna, F. Mora-Guzman, J. A. Caso, et al. 2021. “A Prospective Cross-Sectional Study of Tuberculosis in Elderly Hispanics Reveals That BCG Vaccination at Birth Is Protective Whereas Diabetes Is Not a Risk Factor”. PLoS One 16: e0255194. https://doi.org/10.1371/journal.pone.0255194.
BACKGROUND: Aging increases the risk of tuberculosis (TB) and its adverse outcomes, but most studies are based on secondary analyses, and few are in Hispanics. Diabetes is a risk factor for TB in adults, but its contribution in the elderly is unknown. We aimed to identify the role of diabetes and other risk factors for TB in elderly Hispanics. METHODS: Cross-sectional study among newly-diagnosed TB patients, recent contacts (ReC), or community controls (CoC) totaling 646 participants, including 183 elderly (>60 years; 43 TB, 80 ReC, 60 CoC) and 463 adults (18 to 50 years; 80 TB, 301 ReC and 82 CoC). Host characteristics associated with TB and latent Mycobacterium tuberculosis infection (LTBI) were identified in the elderly by univariable and confirmed by multivariable logistic regression. RESULTS: LTBI was more prevalent among the elderly CoC (55% vs. 23.2% in adults; p0.001), but not in ReC (elderly 71.3% vs. adult 63.8%); p = 0.213). Risk factors for TB in the elderly included male sex (adj-OR 4.33, 95% CI 1.76, 10.65), smoking (adj-OR 2.55, 95% CI 1.01, 6.45) and low BMI (adj-OR 12.34, 95% CI 4.44, 34.33). Unexpectedly, type 2 diabetes was not associated with TB despite its high prevalence (adj-OR 0.38, 95% CI 0.06, 2.38), and BCG vaccination at birth was protective (adj-OR 0.16, 95% CI 0.06, 0.45). CONCLUSIONS: We report novel distinctions in TB risk factors in the elderly vs. adults, notably in diabetes and BCG vaccination at birth. Further studies are warranted to address disparities in this vulnerable, understudied population.
PrabhuDas, Mercy, Rebecca Fuldner, Donna Farber, George A. Kuchel, Joan Mannick, Janko Nikolich-Zugich, Ranjan Sen, et al. 2021. “Research and Resource Needs for Understanding Host Immune Responses to SARS-CoV-2 and COVID-19 Vaccines During AgingInterferon Gamma Release Assays for Detection of Latent Mycobacterium Tuberculosis in Older Hispanic People”. Nature Aging 1: 1073–1077. https://doi.org/10.1016/j.ijid.2021.08.014.
BACKGROUND: Interferon gamma release assays (IGRAs) are used to detect latent Mycobacterium tuberculosis (M.tb) infection (LTBI) in adults, but their performance in older people is not well-established. We evaluated IGRAs for LTBI detection in older Hispanic recent TB contacts (ReC) or community controls (CoC). METHODS: Cross-sectional assessment of LTBI with T-SPOT.TB and/or QuantiFERON-Gold in-tube or -Plus assay in older (>/=60 years) and adult (18-50 years) Hispanic people. RESULTS: We enrolled 193 CoC (119 adults, 74 older persons) and 459 ReC (361 adults, 98 older persons). LTBI positivity increased with age in CoC (19%-59%, P0.001), but was similar in ReC (59%-69%, P=0.329). Older people had lower concordance between IGRAs (kappa 0.465 vs 0.688 in adults) and more inconclusive results (indeterminate/borderline 11.6% vs 5.8% in adults, P=0.012). With simultaneous IGRAs, inconclusive results were resolved as positive or negative with the other IGRA. The magnitude of response to M.tb peptides in IGRAs was similar among age groups, but responsiveness to mitogens was lower in older people. CONCLUSIONS: IGRAs are suitable for LTBI detection in older people. Discordant and inconclusive findings are more prevalent in older people, but results are resolved when IGRA is repeated with a different IGRA test.
Piergallini, T. J., J. M. Scordo, P. A. Pino, L. S. Schlesinger, J. B. Torrelles, and J. Turner. 2021. “Acute Inflammation Confers Enhanced Protection Against Mycobacterium Tuberculosis Infection in Mice”. Microbiol Spectr 9: e0001621. https://doi.org/10.1128/Spectrum.00016-21.
Inflammation plays a crucial role in the control of Mycobacterium tuberculosis infection. In this study, we demonstrate that an inflammatory pulmonary environment at the time of infection mediated by lipopolysaccharide treatment in mice confers enhanced protection against M. tuberculosis for up to 6 months postinfection. This early and transient inflammatory environment was associated with a neutrophil and CD11b(+) cell influx and increased inflammatory cytokines. In vitro infection demonstrated that neutrophils from lipopolysaccharide-treated mice exhibited increased association with M. tuberculosis and had a greater innate capacity for killing M. tuberculosis. Finally, partial depletion of neutrophils in lipopolysaccharide-treated mice showed an increase in M. tuberculosis burden, suggesting neutrophils played a part in the protection observed in lipopolysaccharide-treated mice. These results indicate a positive role for an inflammatory environment in the initial stages of M. tuberculosis infection and suggest that acute inflammation at the time of M. tuberculosis infection can positively alter disease outcome. IMPORTANCE Mycobacterium tuberculosis, the causative agent of tuberculosis disease, is estimated to infect one- fourth of the world's population and is one of the leading causes of death due to an infectious disease worldwide. The high-level variability in tuberculosis disease responses in the human populace may be linked to immune processes related to inflammation. In many cases, inflammation appears to exasperate tuberculosis responses; however, some evidence suggests inflammatory processes improve control of M. tuberculosis infection. Here, we show an acute inflammatory stimulus in mice provides protection against M. tuberculosis for up to 6 months, suggesting acute inflammation can positively affect M. tuberculosis infection outcome.

2020

Powers, Martha, Tiffany R Sanchez, Thomas K Welty, Shelley A Cole, Elizabeth C Oelsner, Fawn Yeh, Joanne Turner, et al. (2020) 2020. “Lung Function and Respiratory Symptoms After Tuberculosis in an American Indian Population. The Strong Heart Study.”. Annals of the American Thoracic Society 17 (1): 38-48. https://doi.org/10.1513/AnnalsATS.201904-281OC.
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Rationale: Permanent lung function impairment after active tuberculosis infection is relatively common. It remains unclear which spirometric pattern is most prevalent after tuberculosis.Objectives: Our objective was to elucidate the impact of active tuberculosis survival on lung health in the Strong Heart Study (SHS), a population of American Indians historically highly impacted by tuberculosis. As arsenic exposure has also been related to lung function in the SHS, we also assessed the joint effect between arsenic exposure and past active tuberculosis.Methods: The SHS is an ongoing population-based, prospective study of cardiovascular disease and its risk factors in American Indian adults. This study uses tuberculosis data and spirometry data from the Visit 2 examination (1993-1995). Prior active tuberculosis was ascertained by a review of medical records. Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and FEV1/FVC were measured by spirometry. An additional analysis was conducted to evaluate the potential association between active tuberculosis and arsenic exposure.Results: A history of active tuberculosis was associated with reduced percent predicted FVC and FEV1, an increased odds of airflow obstruction (odds ratio = 1.45, 95% confidence interval = 1.08-1.95), and spirometric restrictive pattern (odds ratio = 1.73, 95% confidence interval = 1.24-2.40). These associations persisted after adjustment for diabetes and other risk factors, including smoking. We also observed the presence of cough, phlegm, and exertional dyspnea after a history of active tuberculosis. In the additional analysis, increasing urinary arsenic concentrations were associated with decreasing lung function in those with a history of active tuberculosis, but a reduced odds of active tuberculosis was found with elevated arsenic.Conclusions: Our findings support existing knowledge that a history of active tuberculosis is a risk factor for long-term respiratory impairment. Arsenic exposure, although inversely associated with prior active tuberculosis, was associated with a further decrease in lung function among those with a prior active tuberculosis history. The possible interaction between arsenic and tuberculosis, as well as the reduced odds of tuberculosis associated with arsenic exposure, warrants further investigation, as many populations at risk of developing active tuberculosis are also exposed to arsenic-contaminated water.

Oladunni, Fatai S, Jun-Gyu Park, Paula A Pino, Olga Gonzalez, Anwari Akhter, Anna Allué-Guardia, Angélica Olmo-Fontánez, et al. (2020) 2020. “Lethality of SARS-CoV-2 Infection in K18 Human Angiotensin-Converting Enzyme 2 Transgenic Mice.”. Nature Communications 11 (1): 6122. https://doi.org/10.1038/s41467-020-19891-7.
Publisher's Version

Vaccine and antiviral development against SARS-CoV-2 infection or COVID-19 disease would benefit from validated small animal models. Here, we show that transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) by the human cytokeratin 18 promoter (K18 hACE2) represent a susceptible rodent model. K18 hACE2 transgenic mice succumbed to SARS-CoV-2 infection by day 6, with virus detected in lung airway epithelium and brain. K18 ACE2 transgenic mice produced a modest TH1/2/17 cytokine storm in the lung and spleen that peaked by day 2, and an extended chemokine storm that was detected in both lungs and brain. This chemokine storm was also detected in the brain at day 6. K18 hACE2 transgenic mice are, therefore, highly susceptible to SARS-CoV-2 infection and represent a suitable animal model for the study of viral pathogenesis, and for identification and characterization of vaccines (prophylactic) and antivirals (therapeutics) for SARS-CoV-2 infection and associated severe COVID-19 disease.

Ault, R. C., C. A. Headley, A. E. Hare, B. J. Carruthers, A. Mejias, and J. Turner. 2020. “Blood RNA Signatures Predict Recent Tuberculosis Exposure in Mice, Macaques and Humans”. Sci Rep 10: 16873. https://doi.org/10.1038/s41598-020-73942-z.
Tuberculosis (TB) is the leading cause of death due to a single infectious disease. Knowing when a person was infected with Mycobacterium tuberculosis (M.tb) is critical as recent infection is the strongest clinical risk factor for progression to TB disease in immunocompetent individuals. However, time since M.tb infection is challenging to determine in routine clinical practice. To define a biomarker for recent TB exposure, we determined whether gene expression patterns in blood RNA correlated with time since M.tb infection or exposure. First, we found RNA signatures that accurately discriminated early and late time periods after experimental infection in mice and cynomolgus macaques. Next, we found a 6-gene blood RNA signature that identified recently exposed individuals in two independent human cohorts, including adult household contacts of TB cases and adolescents who recently acquired M.tb infection. Our work supports the need for future longitudinal studies of recent TB contacts to determine whether biomarkers of recent infection can provide prognostic information of TB disease risk in individuals and help map recent transmission in communities.

2019

Moliva, J. I., A. P. Hossfeld, S. Sidiki, C. H. Canan, V. Dwivedi, G. Beamer, J. Turner, and J. B. Torrelles. 2019. “Selective Delipidation of Mycobacterium Bovis BCG Enables Direct Pulmonary Vaccination and Enhances Protection Against Mycobacterium Tuberculosis”. Mucosal Immunol 12: 805-15. https://doi.org/10.1038/s41385-019-0148-2.
Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis (TB), is the leading killer due to an infectious organism. Mycobacterium bovis bacillus Calmette-Guerin (BCG) is the only vaccine approved against TB, however, its efficacy against pulmonary TB is poor. While BCG is currently inoculated intradermally, the natural route of M.tb infection is through the lung. Excessive lung pathology caused by pulmonary inoculation of BCG has prevented the use of this immunization route. Here, we show that selective chemical treatment of BCG with petroleum ether removes inflammatory lipids from the bacterial surface while keeping BCG viable. Pulmonary vaccination using this modified BCG attenuated inflammatory responses, prevented immunopathology of the lung, and significantly increased protection against M.tb infection in mice. We further directly linked IL-17A as the responsible contributor of improved immunity against M.tb infection. These results provide evidence that selective removal of cytotoxic lipids from the BCG surface attenuates inflammation and offers a safer and superior vaccine against TB causing less damage post-infectious challenge with M.tb.
Moliva, J. I., M. A. Duncan, A. Olmo-Fontanez, A. Akhter, E. Arnett, J. M. Scordo, R. Ault, et al. 2019. “The Lung Mucosa Environment in the Elderly Increases Host Susceptibility to Mycobacterium Tuberculosis Infection”. J Infect Dis 220: 514-23. https://doi.org/10.1093/infdis/jiz138.
As we age, there is an increased risk for the development of tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) infection. Few studies consider that age-associated changes in the alveolar lining fluid (ALF) may increase susceptibility by altering soluble mediators of innate immunity. We assessed the impact of adult or elderly human ALF during Mtb infection in vitro and in vivo. We identified amplification of pro- oxidative and proinflammatory pathways in elderly ALF and decreased binding capability of surfactant-associated surfactant protein A (SP-A) and surfactant protein D (SP-D) to Mtb. Human macrophages infected with elderly ALF-exposed Mtb had reduced control and fewer phagosome-lysosome fusion events, which was reversed when elderly ALF was replenished with functional SP-A/SP-D. In vivo, exposure to elderly ALF exacerbated Mtb infection in young mice. Our studies demonstrate how the pulmonary environment changes as we age and suggest that Mtb may benefit from declining host defenses in the lung mucosa of the elderly.