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Enzyme immune cells play a key role in defending the host against tuberculosis



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BIRMINGHAM, Ala – Using fresh residual lung tissue of 21 patients and two different mouse models, tuberculosis researchers at the University of Alabama in Birmingham and the African Health Research Institute, or AHRI, have identified a protein that plays a key role in defending the host against this deadly disease .

The research is led by Andris "Adrian" Stein, PhD, professor of microbiology profession who maintains labs in both departments and AHRI in Durban, South Africa. Due to very high rates of tuberculosis or tuberculosis in South Africa, infected human lung tissue is readily available from nearby hospitals, as patients undergo surgery as the last hope for recovery.

Direct examination of microanatomical niches in fresh lung tissue – including healthy and severely affected areas – can then detect differences in the immune response and cell activity in these different regions. Stein and his research team say this unique approach will help identify potential host factors that could be therapeutically focused on limiting severe tissue damage associated with chronic lung TB disease. This dangerous lung tissue, including the lungs infected with TB-resistant bacteria or extensive drugs, is carefully handled in an advanced biosafety laboratory in AHRI, as only one to three tuberculosis in the aerosol drop can cause infection. TB infections by the bacteria Micobacterium tuberculosis, or Mtb, kill about 1.3 million people per year.

Stein and colleagues have managed to separate different types of cells found in different niches of human freshly harvested TB and characterize these cells for the production of protein heme oxygenase-1. Heme oxigenase-1 or HO-1 is an enzyme that protects cells from harmful reactive oxygen or nitrogen intermediates; HO-1 can also control inflammatory reactions.

The researchers found that HO-1 in pulmonary TB lungs was expressed primarily from myeloid immune cells, including neutrophils and macrophages, and that levels of HO-1 in these cells were directly proportional to protection against TB pathophysiology.

In particular, there was a higher proportion of neutrophils and macrophages that produced HO-1 in non-infected lung areas than in diseased areas, and those cells in non-infected areas produced more HO-1 than cells in diseased areas. As a consequence, the lack of HO-1 protection in diseased areas has allowed the production of myeloid cells of destructive reactive oxygen and nitrogen. What makes these findings clinically relevant is that HO-1 is necessary in humans, but not in mice, indicating the importance of testing human lung tissue to supplement animal TB models.

"To my best of all, this extensive analysis of fresh resection lung tissue of tuberculosis is the first of its kind, since the lungs are scarce," said Stein.

This finding in humans is supported by two HO-1 deficient mice models that have shown that HO-1 is necessary for the control of infiltration and myeloid cell inflammation to protect against TB progression. One mouse model was the global nail of the HO-1 gene; The other model was HO-1 kicot only in myelogenous cells. In both models, nailed mice had more susceptibility to Mtb infection – mice-nipples had died earlier and had higher Mtb loads in the lungs and spleen. Nailed mice also increased infiltration of immune cells and cytokine levels, a protein that signals cells that regulate or stimulate immune responses.

In all, findings from pulmonary lung and mouse models have shown that HO-1 expression, especially within myeloid cells, is critical to host defense against the progression of Mtb disease. For patients with TB, Stein says, research suggests that finding ways to improve HO-1 activity can limit immunopathology during active TB disease.

This research was published on November 13 in the journal Cell Reports, and also appears on the front of the magazine.

Two laboratories, a separate world

Stein is a professor and primary faculty at the Department of Microbiology at UAB and holds a research laboratory at UAB. He is also a regular investigator at AHRI and lives in Durban, South Africa. Visiting UAB at least six times a year.

Stein is responsible for creating a program where students from the VSS and Medical School get a unique opportunity to visit and conduct research in AHRI as part of a research internship. "When you go to separate areas in Africa and see the destruction of the disease," Stein said, "It only changes you. That makes a difference."

Working in AHRI gives students, especially those from the medical training program, an excellent opportunity to work in state-of-the-art research facilities located in the country with one of the greatest burdens in the world. Seven UAB Ph.D. and M.D. / Ph.D. students were researching in Styen's Laboratory in Durban, within the annual program of the summer research program UAB-AHRI.

Stein & # 39; s Cell Reports The work follows an earlier study using pulmonary lung tissue. This study, published last May in Immunology Immunization by Stein and colleagues, examined the distribution of iron in diseased lungs. Iron is an essential factor for the growth and virulence of Mtb, but little is known about how the host controls the availability of iron during infection.

Stein and colleagues have found an important role for ferritin H iron protein in TB control, which is directly linked to HO-1. The researchers found that a mouse model that had a heavy chain micronucleotide heavy chain ferrugin gene was more susceptible to TB, as indicated by an increased number of Mtb in the organs, the spread of Mtb behind the lungs, and reduced survival. Namely, reduced levels of iron have been found in pulmonary TB lungs.

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The Cell Reports paper, "Microanatomical distribution of myeloid haem oxigenase-1 protects against free radicals mediated immune function in human pulmonary tuberculosis", is a result of team work conducted by the first author of Krishna C. Chinta. The study included other members of Stein's team: Vikram Saini, Joel N. Glasgow and Vineel P. Reddi at the Department of Microbiology in Belgrade and Aejazur Rahman, Kijevershen Nargan and Gordon Vells at AHRI. Vikram is now at the All Indian Institute of Medical Science, New Delhi, India.

In Alabama, they collaborated with Anupam Agarval, executive vice president of IT and director of the Department of Nephrology at UAB and James George, a professor at the Department of Cardiothoracic Surgery, Department of Surgery, UAB, were key to the project, Stein said. The research was attended by members of Agarval Laboratory Jeremie M. Lever and Amie Trailor. Also, the contribution of co-author Pratistadevi K. Ramdial and Rajhmun Madansein, Central Hospital Inkosi Albert Luthuli and Kwazulu-Natal University, Durban, South Africa.

Together with the above-mentioned researchers, co-authors in Cell Reports paper are Rian M. Vells, Department of Microbiology (currently at the University of Minnesota); Shepherd Nhamoiebonde and Alasdair Leslie, AHRI, Durban, South Africa; Gene P. Siegal, Directorate of Pathology; and Veena B. Antoni and Jessi Deshane, Department of Lung, Allergic and Critical Care Medicine, Department of Medicine at the company.

Support for this work came from the National Institute of Health grants AI111940, AI127182 and DK59600; Bill and Melinda Gates Foundation Award OPP1130017; and the South African Medical Research Council. Support also came from the AIDS Research Center UAB UAB and the Center for Free Radical Biology.

At UAB, Agarval is holding Marie S. Ingalls Endoved Chair in Nephrology Leadership, George holds the Cardiovascular Surgical Research Desk, and Siegal holds Robert V. Movri's endowed profession in pathology.

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