Virus Egress Pathways

National Heart, Lung, And Blood Institute

Investigators

Linked publications & trials

Abstract

Much of the field of virology has long viewed the cell as a passive supplier of viral building blocks and focused on how viruses exploit individual cellular enzymes for transcription of their messenger RNAs or translation of the viral proteins. Dr. Nihal Altan-Bonnet using the dynamic tools of live-cell microscopy has made fundamental discoveries, revealing how viral exploitation of the host goes beyond individual molecules and rather induces a complete shake up of cell physiology and architecture. As an outsider with a background in cellular biology and biophysics, Dr. Altan-Bonnet came into the field of virology without any allegiance to a particular virus- something unusual in this field as most virologists focus on the study of one virus. Instead she intentionally sought to study a wide variety of different viruses in order to search for general principles and common strategies viruses employ to exploit the host cell. This broader approach resulted in several groundbreaking discoveries. The first of which was the discovery that many viruses alter the host lipid metabolism to assemble viral replication platforms. Specifically, Dr. Altan-Bonnet showed that a host encoded lipid kinase, phosphatidyl inositol 4-kinase, can be hijacked by multiple different RNA viruses (including poliovirus, hepatitis C, Enterovirus D68, Rhinovirus). The reason for multiple viruses to converge on this lipid kinase she showed was to generate PI4P lipid enriched replication compartments where this PI4P lipid was used as a membrane dock to recruit, stabilize and stimulate the catalytic activities of viral replication enzymes. Her studies have been the basis of multiple initiatives by pharmaceutical companies (Glaxo, Novartis) and universities (Project Four Stanford ViRX) to develop small molecules against host PI4 kinases as panviral targets. Dr. Altan-Bonnet 's second groundbreaking discovery was the identification of a new form of viral infectious unit: viruses traveling en masse, cloaked inside vesicles. Before this discovery, it was not only assumed that viruses traveled as free single particles from host to host but this form of travel was considered to be the most virulent as it allowed viruses to spread wide and infect as many hosts as possible. Nihals findings challenged the classical concept of virus transmission as individual units of infection and accounted for their evolution of populations as quasi-species or viral variants. Dr. Altan-Bonnet revealed that many different viruses exit cells without lysis, inside extracellular vesicles and most remarkably as multiple virus particles all traveling together. She went on to show that this form of transmission is much more infectious and virulent than viruses as single particles because by entering cells in high numbers they could easily overcome barriers to replication- barriers from not only the host side but also intrinsic barriers such as mutant viral variants or quasi-species that alone would be handicapped but by traveling en masse benefit from cooperative behavior. Additionally, cloaked under a vesicular membrane, viruses were protected from inflammatory and/or neutralizing immune responses: this is particularly significant for enteroviruses that must traverse the harsh environment of the gastrointestinal tract while maintaining their infectiousness. Recently Dr. Altan-Bonnet has demonstrated that these extracellular vesicles carrying viruses are highly stable in the gastrointestinal tract, in stool, in aerosol and are copiously shed by humans and animals. Dr. Altan-Bonnet's investigations into what makes viruses efficient at transmission led also to her recent discovery of an entirely new and likely more public health relevant transmission route for the enteric viruses norovirus, rotavirus and astrovirus, which combined infect 1.5 billion people globally causing much mortality and morbidity (not to mention economic hardship). Until her findings, enteric viruses were thought to solely replicate in intestines and spread through the oral-fecal route among hosts. She demonstrated that these enteric viruses replicate in salivary glands robustly ( on par with intestines) and spread through saliva, not only among individuals but also between mothers and infants through suckling. This finding potentially opens the way to simpler diagnostics for these viruses, such as saliva tests, and also may prompt revision of public health sanitary practices, which until now have been solely focused on limiting viral transmission by the oral-fecal route, to include masking. Finally during the COVID-19 pandemic, Dr. Altan-Bonnet applied her imaging skills to peer inside coronavirus infected cells to reveal how these viruses exit from cells and spread to others- an area that has remarkably not been studied. Most viruses, including hepatitis C, rely on the biosynthetic secretory pathway (e.g. Golgi apparatus) to exit out of cells and this was assumed to be the case for coronaviruses too. But Nihal discovered that these viruses are unique in that they piggy-back on a more exotic cellular pathway, lysosomal exocytosis, to exit from the cells. In the process, viruses can evade cell defenses as their passage through the lysosomal pathway inactivates lysosomal protein degradation and alter cellular antigen presentation. This discovery of a fundamental aspect of the coronavirus lifecycle, using lysosomes for exit, maybe one, if not the root cause, of the system wide immune dysfunction exhibited by COVID patients. To conclude, the extraordinary circumstances brought upon by the recent pandemic, emphasize even more the need for investigations, like Dr. Altan-Bonnet s, into the general principles and molecular/cellular details of host-pathogen interactions.