With input from Dr Monica Vasudev

1273:  A form of inflammatory cell death, termed panoptosis, incites the storm of cytokines, or inflammatory proteins thus causing critical illness in COVID-19.

As per Thirumala-Devi Kanneganti of St. Jude Childrens Research Hospital, during inflammatory cell death, cells spew out their contents instead of neatly packaging them away, as is seen during routine cell death.

Neighboring cells identify the cytokines and the other unexpected debris as a danger sign, and they can respond by secreting more cytokines, thus allowing the cytokine storm to build.

Synergy between two cytokines, TNF-alpha and IFN-gamma, is the reason behind panoptosis in COVID-19.

Mice given TNF-alpha and IFN-gamma were found to develop the symptoms and organ damage of COVID-19 and died rapidly.

Treatment with antibodies that neutralize these two cytokines appeared to protect the mice from death, not just from COVID-19, but also other life-threatening illnesses that involve cytokine storms, such as sepsis. [Reuters Excerpts]

1. Programmed cell death plays pivotal roles in organismal development and host defense.
2. There is mechanistic overlap and extensive, multifaceted crosstalk between pyroptosis, apoptosis, and necroptosis - the three programmed cell death pathways traditionally considered autonomous.
3. Increasing evidence, along with the identification of molecules controlling the concomitant activation of all three pathways by pathological triggers, has given way to the development of the concept of PANoptosis.
4. During PANoptosis, there isinflammatory cell death through the collective activation of pyroptosis, apoptosis, and necroptosis, which can circumvent pathogen-mediated inhibition of individual death pathways.
5. Activation of PANoptosis can occur by bacterial and viral triggers.
6. Infection of macrophages with some viruses results in robust cell death and the hallmarks of PANoptosis activation.
7. Combined deletion of the PANoptotic components caspase-1 (CASP1), CASP11, receptor-interacting serine/threonine-protein kinase 3 (RIPK3), and CASP8 protects macrophages against cell death induced by these pathogens, while deletion of individual components yields diminished or no protection.
8. RIPK1, RIPK3, CASP8, NLRP3, ASC, and FADD can interact to form a PANoptosome
9. Molecules from the pyroptotic, apoptotic, and necroptotic cell death pathways interact to form a single molecular complex, termed the PANoptosome.

[Front Cell Infect Microbiol. 2020; 10: 237.]

Dr KK Aggarwal

President CMAAO, HCFI and Past National President IMA