Apoptosis inhibitors show promise in severe TB models

Macrophage and neutrophil apoptotic cell death have been demonstrated to confer resistance to severe tuberculosis (TB) infection in preclinical mouse models of the disease, according to an Australian study reported in the July 12, 2021, edition of Immunology.

Led by researchers at the Walter and Eliza Hall Institute (WEHI) and University of Melbourne, the study identified apoptotic pathways as new TB therapeutic targets and showed that TB-infected cells could be killed using existing antagonists of inhibitors of apoptosis proteins (IAPs).

"To my knowledge, this is the first report that IAP antagonists may have potential for treating TB," said study leader Marc Pellegrini, professor and joint head of the Division of Infectious Diseases and Immune Defence at WEHI.

TB represents a significant global burden of morbidity and mortality, with an estimated 10 million people each year developing the disease, which remains a leading cause of infectious mortality.

Standard anti-TB treatment requires a regimen of at least 6 months of combined antibiotics, and multidrug-resistant (MDR) TB is becoming an increasingly grave threat to public health worldwide.

"MDR TB, in which Mycobacterium tuberculosis is resistant to many but not all drugs, is increasing in prevalence worldwide," noted Pellegrini.

"This has multiple drivers, including inappropriate treatments, the inability to mitigate transmission of resistant bacteria, and the length and complexity of treatment compromising patient compliance."

At the 2021 IAS Meeting on HIV Science, held this week virtually and in Berlin, investigators presented positive news from two trials for treatment of MDR TB.

Researchers reported data from the TB-PRACTECAL trial, which had been stopped early in March, 2021, after its data safety monitoring board concluded that the TB-PRACTECAL regimen was clearly superior to the current treatment regimens for MDR TB, driven by high rates of discontinuations in the standard-of-care arm.

In addition, the ZeNIX study demonstrated a roughly 90% cure rate of highly resistant TB through a 6-month combination treatment with bedaquiline, pretomanid and linezolid, and it was first demonstrated in the NIX trial that it could be maintained with lower doses of linezolid, reducing the toxicity of the regimen.

Nevertheless, there remains an urgent need for effective new approaches and ideally, a shorter treatment regimen.

Apoptosis

A type of programmed cell death, apoptosis can robustly defend against intracellular pathogens by directly killing infected immune cells and the pathogens within them.

However, M. tuberculosis has been reported to restrict apoptosis in macrophages in vitro, which has led to it being widely overlooked as a host-protective mechanism in TB, despite a lack of in vivo evidence.

In the new Immunology study, the authors revealed how M. tuberculosis-infected cells can die and demonstrated that enhancing apoptosis using IAPs could reduce disease severity in preclinical mouse models.

Using gene editing tools such as CRISPR, the researchers sequentially deleted the key death receptor-mediated and B-cell lymphoma 2 (BCL-2)-regulated apoptosis pathways in these models, to demonstrate their roles in controlling infections in vivo.

"The mouse model doesn't exactly reflect the breath of TB in humans, but does replicate insidious progressive pneumonia, so is a very valuable tool for identifying new TB therapies, with nearly all new drugs being tested in animals," said Pellegrini.

The apoptosis pathways were shown to mediate protection against TB by eliminating distinct populations of infected macrophages and neutrophils and priming T-cell responses, opening up new avenues for disease control.

"Using gene-targeted mice lacking critical regulators of host apoptosis, we were able to show that intrinsic and extrinsic apoptotic pathways, but not those related cell death pathways such as necroptosis or pyroptosis, mitigated severe disease," said Pellegrini.

For example, "mice lacking the extrinsic apoptosis initiator, caspase 8, were shown to develop early and severe disseminated TB pneumonia and TB in the spleen," he told BioWorld Science.

The researchers then demonstrated that apoptotic pathways could be targeted therapeutically with drugs that antagonize IAP proteins, which were initially developed for treating cancer, to promote clearance of M. tuberculosis in the mice.

"Many of these compounds are already in clinical trials for other types of disease, mainly cancer, and have proven to be safe and well-tolerated," said study first author Michael Stutz, a PhD student at WEHI at the time of the study.

"We showed that these IAP antagonists, which indirectly promote caspase 8 activity, were able to preferentially kill host cells harboring M. tuberculosis, thereby preventing its replication and transmission to new cells," said Pellegrini.

"Normally antibiotics need to be taken for many months to reduce the burden, but we found that several weeks of IAP inhibition could achieve the same."

The researchers further demonstrated that the degree of TB clearance and hence reduction of disease increased with prolonged treatment duration and that these findings could be replicated using different IAP inhibitors.

"If these compounds were progressed for treating tuberculosis, we predict that they would be most effective if used with existing antibiotic treatments," suggested Stutz.

"We generally combine new therapies with existing therapies to maximize benefit and reduce the time to cure," agreed Pellegrini.

"While it might be possible to use IAP inhibitors as effective monotherapies for MDR TB, for the most part I envisage adding IAP to existing antibiotics where possible to ensure rapid and effective cure."

Moreover, "unlike antibiotics, IAP inhibitors kill the cells that the TB bacteria need to replicate and survive," he said, adding, "by targeting the host rather than the microbe, the chances of resistance developing are incredibly low."

On safety, he pointed out that the IAP inhibitors have been well tolerated in clinical trials for cancer, "but as with all new therapies, further clinical trials will be needed to ensure safety in people with TB, which might take 5-7 years prior to possible approval by regulatory authorities."

Together, study findings advance our understanding of host-protective responses to TB and reveal apoptotic pathways that may be targetable for treating TB including increasingly prevalent MDR TB.

However, "there are many pathogens similar to M. tuberculosis, in that they replicate inside cells and create a microenvironment. Therefore, we are highly interested in and committed to understanding whether the discoveries made here may be applicable to such other infections."

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