First 3-D view of TB granulomas alters paradigm of their shape and
formation

Date:
July 28, 2021
Source:
University of Alabama at Birmingham
Summary:
MicroCT of infected human lung tissue, along with histology and
immunohistochemistry, was used to construct images of TB granulomas,
airways and vasculature.



FULL STORY ==========================================================================
For 70 years, clinicians thought they knew the shape of tuberculosis
granulomas in the lungs of patients. Histology -- the study of microscopic structures in thin slices of lung tissue in the 1940s and 1950s --
showed round features, and researchers intuitively assumed that meant
the granulomas were spherical or ovoid.


==========================================================================
That long-lived paradigm is now shown to be wrong, in a study by
researchers at the University of Alabama at Birmingham and the Africa
Health Research Institute, or AHRI, Durban, KwaZulu-Natal, South
Africa. The historical histology, essentially, was a two-dimensional
look at structures, similar to cutting a very thin slice through a tree
branch, a slice that would look round or oval.

The new research has created a three-dimensional view of diseased lung
tissue from tuberculosis patients, using micro-computed tomography,
or microCT. This revealed that the larger granulomas were anything but
round -- rather they had complex, branched shapes. One granuloma looked somewhat like a ginger root, another like a cluster of early buds on a
cherry tree, before the blossoms appear. The tuberculosis granulomas
showed marked heterogeneity in shape, volume and number in the lung
sections. (See link to study below for videos of the three-dimensional
views.) A granuloma is an aggregation of immune cells summoned in
response to chronic inflammation. In tuberculosis, the granulomas are
often necrotic, meaning they are a mass of formless dead debris.

Researchers led by Adrie Steyn, Ph.D., a UAB professor of microbiology and
a member of the AHRI, used microCT, histology and immunohistochemistry
to construct three-dimensional views of necrotic granulomas, and also vasculature and airways. This yielded an unanticipated insight into the
spatial organization of tuberculosis granulomas in relation to airways
and vasculature.

"Unlike depictions of granulomas as simple spherical structures,"
Steyn said, "human necrotic granulomas exhibit complex, cylindrical,
branched morphologies that are connected to the airways and shaped by
the bronchi." Steyn says these visualizations have three impacts. They highlight the likelihood that a single structurally complex lesion could
be mistakenly viewed as multiple independent lesions when evaluated in
two dimensions. Second, the lack of vascularization within obstructed
bronchi establishes a paradigm for anti-mycobacterial drug tolerance,
since the microbes are protected from a full delivery of blood-borne bactericidal drugs. Third, the results suggest that a bronchogenic spread
of the Mycobacterium tuberculosis pathogen re-seeds the lung.



========================================================================== "Hence, our findings provide a rationale for considering aerosolized
anti- tuberculosis drug delivery," Steyn said. "This approach could allow delivery of high, local concentrations of drugs directly into granulomas
or cavities in the lung, possibly reducing treatment times, systemic
dosing and toxicity." Infections by the Mycobacterium tuberculosis
bacterium kill about 1.3 million people a year.

Steyn and colleagues say, to their knowledge, this is the first three- dimensional description of granulomas, airways and vasculature for any bacterial pulmonary pathogen.

Infected human lung tissue is readily available for study in Durban
because that part of Africa is an epicenter for tuberculosis. The Inkosi
Albert Luthuli Central Hospital, not far from AHRI, does resection
surgeries to remove diseased lobes from tuberculosis patients. MicroCT
is similar to the common medical CAT scans but has a much finer
resolution. The researchers used resolutions as small as 12 microns,
which is about the thickness of a sheet of plastic kitchen wrap. Research leader Steyn maintains labs at UAB and the AHRI.

He lives in Durban and visits UAB about six times a year.

The study, "myCT Analysis of the Human Tuberculous Lung Reveals Remarkable Heterogeneity in 3D Granuloma Morphology," was published in the American Journal of Respiratory and Critical Care Medicine. The journal also
published an editorial on the Steyn study.

Co-authors with Steyn are Gordon Wells, Kievershen Nargan and Kapongo
Lumamba, AHRI; Joel N. Glasgow, UAB Department of Microbiology; Rajhmun Madansein and Kameel Maharaj, Inkosi Albert Luthuli Central Hospital
and University of KwaZulu-Natal, Durban, South Africa; Robert L. Hunter, University of Texas Health Sciences Center at Houston; Threnesan Naidoo,
Inkosi Albert Luthuli Central Hospital; and Llelani Coetzer, Stephan Le
Roux and Anton du Plessis, Stellenbosch University, South Africa.

Support came from National Institutes of Health grants Al111940,
AI134810, AI137043, AI138280 and A127182; a Bill and Melinda Gates
Foundation Award; and pilot funds from the UAB Center for AIDS Research,
the UAB Center for Free Radical Biology, and the Infectious Diseases and
Global Health and Vaccines Initiative. Support also came CRDF Global,
the South African Medical Research Council and a South Africa National
Research Foundation BRICS Multilateral grant.

========================================================================== Story Source: Materials provided by
University_of_Alabama_at_Birmingham. Original written by Jeff
Hansen. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Gordon Wells, Joel N Glasgow, Kievershen Nargan, Kapongo Lumamba,
Rajhmun
Madansein, Kameel Maharaj, Robert L Hunter, Threnesan Naidoo,
Llelani Coetzer, Stephan Le Roux, Anton du Plessis, Adrie
J.C. Steyn. myCT Analysis of the Human Tuberculous Lung Reveals
Remarkable Heterogeneity in 3D Granuloma Morphology. American
Journal of Respiratory and Critical Care Medicine, 2021; DOI:
10.1164/rccm.202101-0032OC ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/07/210728140351.htm

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