Page 43 - Annual report 2021-22

Annual Report 2021-22 |

Krishnendu Chakraborty

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Krishnendu Chakraborty’s group is interested in providing molecular insights into mitochondria driven
control of inflammation.

Acute lung injury (ALI) and Acute Respiratory Distress Syndrome (ARDS) are leading causes of mortality
around the world. Although the exact pathophysiology remains elusive, unwarranted inflammation is
considered a major underlying cause. The immune response during ALI/ARDS can be divided into two
broad phases, the initial hyper-inflammatory phase followed by a late immunosuppressive phase. For
decades, the hyperinflammatory phase, associated with unregulated cell death and tissue damage,
leading to hypoxia was considered the major cause of mortality in ARDS. However, recent literature
has highlighted the importance of secondary infections in the immunosuppressive phase as a leading
cause of late-phase deaths in ARDS. Disproportioned cell death during ALI/ARDS leads to the release
of DAMPs (damage-associated molecular patterns) into the extracellular microenvironment and an
increased level of the mitochondrial-DAMP cardiolipin (CL) has been reported in lung fluids of patients
suffering from severe pneumonia. Earlier, Krishnendu Chakraborty’s group has shown that CL can
impair inflammation resolution in pneumonia by suppressing IL-10 production through K107
SUMOylation of PPARgamma. Recently, they dissected the precise mechanism for this suppression by
identifying the specific E3 SUMO ligase responsible and the role of JNK-MAPK mediated PPARgamma
S112 phosphorylation in ensuring the specificity of this mechanism. Furthermore, by repurposing a
clinically tested peptide inhibitor targeting JNK-MAPK, they blocked these post-translational
modifications (PTMs) of PPARgamma and rescued IL-10 expression, to improve survival in murine
pneumonia models.

Currently, this group is exploring how CL might influence the late immunosuppressive phase of
ALI/ARDS. The preliminary data generated by RNA-seq analysis showed elevated expression of IRAK-
M and A20 (two critical negative-regulators of TLR signaling) in the lung tissue of LPS+CL administered
mice in comparison to only LPS treatment, indicating a potentially immune-compromised condition
due to the impaired TLR response. Reduced pro-inflammatory cytokine production and increased
bacterial load in the lung of LPS+CL treated mice further support this possibility. They are currently
exploring the underlying mechanism of this CL-mediated immunosuppression.

Klebsiella pneumoniae (KP) is one of the major etiological agents of nosocomial pneumonia during the
late immunosuppressive phase of ARDS. Recently, mortality due to KP infection has increased many
folds due to the emergence of carbapenemase-producing KP (KPC), limiting therapeutic options
available against it. In this situation tweaking the host’s own immune response in favor of the host’s
defense would be of paramount importance. Therefore, it was important to explore the underlying
complexities of host-pathogen interactions during KPC infection. KPC strain- ST258 has been involved
in multiple epidemics around the globe, associated with high mortality. Interestingly, KPC incites an
immune response different from the classical KP strain (ATCC 43816). This was highlighted by a recent
study, which found that ST258 is resistant to neutrophils and CCR2+ monocytes, which are essential
for resolution, whereas the classical strain requires a neutrophilic response for its clearance. In
addition, although ST258 is highly virulent in humans, it has negligible virulence in mice, unlike the