# Immunotherapy of KPC Infection

> **NIH NIH R01** · TULANE UNIVERSITY OF LOUISIANA · 2022 · $486,421

## Abstract

A continued and emerging threat to human health are multi-drug resistant bacterial infections. Among these
threats, carbapenemase producing strains of Klebsiella spp has been recognized by the World Health
Organization and the Centers for Disease Control has a global threat to human health particularly in the
hospital setting. Clinically these infections often appear to be opportunistic infections affecting patients with
co-morbidities such as immunosuppressive drugs, poor performance status, mechanical ventilation, and
kidney disease. In addition, hematologic malignancies and solid organ and stem cell transplant recipients are
at risk. Recently hyervirulent strains with mucoid capsule have been reported but carriage rates in areas of
Asia can approach 5% in stool, which far exceeds the rate of clinical infection, suggesting host factors are
important. Pulmonary inoculation of the non-mucoid ST258C4 strain was avirulent in WT mice as well as
Rag-/- mice which lack T and B cells. In contrast Rag2, Il2rg -/- which additionally lack NK cells and innate
lymphoid cells, were susceptible to infection and had mortality, which was associated bacterial dissemination.
Single cell RNAseq of lung tissue demonstrated that NK cells and group 3 innate lymphoid cells were
associated with bacterial clearance. In preliminary studies, only dual antagonism of both NK cells and group 3
ILCs resulted in ST258 infection suggesting these two cell populations are key to host defense against this
organism. As IL-22:Fc is clinical trial for gut graft versus host disease and diabetic foot ulcers, we investigated
if systemic IL-22:Fc administration could be used as immunotherapy. Preliminary studies show that IL-22:Fc
can substantially reduce bacterial burdens in mice susceptible Rag2-/-, Il2rg -/- mice. To examine if these
cellular responses were perturbed by clinically relevant immunosuppression, we administered FK506, which is
used in solid organ transplant, to mice. FK506 treatment increased susceptibility to infection and reduced
IFNg, Il17a, and Il22 in the lung. Thus, we have developed genetic and pharmacological models that allow us
to propose the following testable hypothesis: ST258 C4 infection requires NK cells and group 3 ILC cells for
clearance and these populations are inhibited by calcineurin inhibition. Moreover we hypothesize that cytokine
based immunotherapy can be developed to augment endogenous host responses to clear this infection. We
will test these hypotheses with the following specific Aims using both non-mucoid (C4) as well as hypermucoid
strains of KPC: Specific Aim 1. Test the prediction that both NK cells and group 3 innate lymphoid cells are
required for lung mucosal immunity against Kpc infection. Specific Aim 2. Develop a clinically and
pharmacologically relevant model of Kpc infection. Specific Aim 3. Test the prediction that systemic or local
immunotherapy is effective in controlling Kpc infection.

## Key facts

- **NIH application ID:** 10443796
- **Project number:** 5R01AI149119-03
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** JAY K KOLLS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $486,421
- **Award type:** 5
- **Project period:** 2020-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10443796

## Citation

> US National Institutes of Health, RePORTER application 10443796, Immunotherapy of KPC Infection (5R01AI149119-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10443796. Licensed CC0.

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