The Fascinating World of Bat Biology and Viral Resilience

Why are bats one of the most studied creatures? Bats possess unique adaptations that contribute to their impressive resistance to viral infections. With diverse species that diverged over 50 million years ago, evolutionary pressures have led to specific adaptations across different bat species. Let's explore some key mechanisms behind their robust immune systems.

1. DNA Sensors

Many bat species lack the entire PYHIN gene family. Pyrin and hematopoietic interferon-inducible nuclear domain (PYHIN) proteins detect DNA from pathogens or the host's damaged DNA, sparking an inflammatory response. The absence of this gene family might explain bats' ability to control harmful virus-induced inflammation (1).

2. Viral Antagonism Escape

While some pathogen sensors are missing, others have evolved. Protein kinase R (PKR) proteins detect double-stranded RNA, signaling a viral infection and initiating an antiviral response. Many viruses, including poxviruses, herpesviruses, and influenza viruses, have developed ways to interfere with PKR function. Researchers believe that the diversification of PKR genes helps bats evade this viral interference (2).

3. Interferons

Interferons are essential players in the antiviral response. Bat species show variations in interferon genes and their regulation. Some bats exhibit constant expression of interferon-α, while others have expanded less-studied interferon-ω genes.

4. Inflammasomes

Bat ASC2 (apoptosis-associated speck-like protein containing a CARD domain) inhibits inflammasome activation. Although inflammasome signaling is crucial for the antiviral response, overactivation can lead to mortality from viruses like influenza. Studies have shown that bat ASC2 increases survival rates in influenza-infected mice (2).

5. Possible Self-vaccination

A recent study on bat induced pluripotent stem cells found an unusually high number of endogenous viral sequences. Researchers suggest that these sequences might serve to defend against viruses and microbes by encoding viral proteins through a sort of self-vaccination mechanism.

6. Undiscovered Mechanisms

With over 1,400 bat species and few fully sequenced genomes, many potential antiviral or anti-inflammatory mechanisms remain undiscovered. The Bat1K gene sequencing initiative aims to uncover these hidden secrets.

Translating Findings into Therapies

Turning these genetic insights into therapies is no small feat. According to Arinjay Banerjee, "Understanding the molecular changes that drive specific immunological characteristics in bats can help design small molecules or synthetic proteins to mimic those effects in humans."

The Research Journey

A research team led by Linfa Wang at the Duke-National University of Singapore (NUS) Medical School is making strides in this area. Wang, often called "The Batman," has studied bats and their viruses for over 20 years. One of his students, Matae Ahn, joined the team after becoming fascinated by bat research. The team focused on what makes bats unique. Bats handle flight stress, show high viral tolerance, and have remarkable longevity. They hypothesized that these traits were linked and began investigating the inflammasome, a multiprotein complex involved in stress, infection, and aging responses. Their research revealed that potent inflammasome stimulators didn't strongly activate bat inflammasomes. They found high expression of ASC2, a protein previously thought to exist only in primates, in all 13 bat genomes they examined. This discovery led to further investigation into ASC2's role in immunity and inflammation (1).

To test ASC2's effects, researchers engineered human cells to express either bat ASC2 or human ASC2. They found that bat ASC2 was more effective at reducing inflammatory responses. They then created a mouse model with the bat ASC2 gene, which showed increased survival rates when infected with influenza. Researchers identified four crucial bat ASC2 residues responsible for its enhanced inflammasome inhibition. By mutating these regions in human ASC2, they created Hupa4 ASC2, effective at reducing inflammation in human cells. While this peptide isn't highly bioavailable, it could be applied to surface tissues or developed into small molecules for other applications (1). 

Unraveling Bat Immunity: Interferons in Human Cells

Banerjee's work on another bat species highlights how interferons may be key to bats' disease resistance. His research showed that while MERS-CoV suppresses the IFN-β response and results in higher viral loads in human cells, big brown bat cells exhibit a robust IFN-β response, leading to lower viral loads. This effect is likely influenced by the bat interferon regulatory factor 3 (IRF3). Banerjee and his team continue to explore how this virus persists in bat cells and tissues.

Exploring Genetic Secrets 

Lucie Etienne, from the International Center for Infectious Disease Research, also dives into the evolutionary battle between bats and viruses. Her team discovered that some mouse-eared bats have two copies of the gene encoding protein kinase R (PKR), an antiviral factor. This is unusual since all other mammals have just one copy. This could give these bats an edge in evading viral inhibitors, potentially explaining their high number of zoonotic viruses.

Thomas Zwaka from the Icahn School of Medicine at Mount Sinai took a unique path to bat biology, starting with stem cell research. In January 2020, virologist Adolfo García-Sastre suggested using lung cell models to study the new respiratory virus spreading in China. This sparked Zwaka's interest in SARS-CoV-2 and its probable bat origin. He wondered if bat iPS cells differentiated into lung cells would show a different immune response compared to human cells.

"Everyone sees the excitement and novel biology of bats," said Zwaka. "It's almost like a gold rush—every discovery reveals something fascinating" (2). 

Sources

Jacquet, S., Culbertson, M., Zhang, C., El Filali, A., De La Myre Mory, C., Pons, J. B., ... & Etienne, L. (2022). Adaptive duplication and genetic diversification of protein kinase R contribute to the specificity of bat-virus interactions. Science advances, 8(47), eadd7540.

Thomazy, Hannah, PhD. "Turning on the Bat Signal." Spring, 2024. The Scientist. https://www.the-scientist.com/turning-on-the-bat-signal-71700