Innate Lymphoid Cells and Natural Killer Cells in Bacterial Infections: Function, Dysregulation, and Therapeutic Targets

Abstract

Infectious diseases represent one of the largest medical challenges worldwide. Bacterial infections, in particular, remain a pertinent health challenge and burden. Moreover, such infections increase over time due to the continuous use of various antibiotics without medical need, thus leading to several side effects and bacterial resistance. Our innate immune system represents our first line of defense against any foreign pathogens. This system comprises the innate lymphoid cells (ILCs), including natural killer (NK) cells that are critical players in establishing homeostasis and immunity against infections. ILCs are a group of functionally heterogenous but potent innate immune effector cells that constitute tissue-resident sentinels against intracellular and extracellular bacterial infections. Being a nascent subset of innate lymphocytes, their role in bacterial infections is not clearly understood. Furthermore, these pathogens have developed methods to evade the host immune system, and hence permit infection spread and tissue damage. In this review, we highlight the role of the different ILC populations in various bacterial infections and the possible ways of immune evasion. Additionally, potential immunotherapies to manipulate ILC responses will be briefly discussed.

Cryptococcus escapes host immunity: What do we know?

“…Innate lymphoid cells (ILCs), a vital part of the innate immune system, are stemmed from lymphoid lineages lacking PRRs ( Spits et al., 2013 ). Although ILCs fail to recognize antigens specifically, they contribute immediately in tissue homeostasis, pathological inflammation, and immunity against infections through cytokine stimulation bringing about direct subsequent innate and adaptive immune responses ( Elemam et al., 2021 ). ILCs are generally classified into three major subgroups of innate lymphoid cells: group 1 (ILC1s), including natural killer (NK) cells, group 2 (ILC2s), and group 3 (ILC3s) ( Spits et al., 2013 ).…”

“…ILCs are generally classified into three major subgroups of innate lymphoid cells: group 1 (ILC1s), including natural killer (NK) cells, group 2 (ILC2s), and group 3 (ILC3s) ( Spits et al., 2013 ). ILC1s drive type 1 immune responses which respond to intracellular pathogenic bacteria and fungi with the secretion of IFN-γ and TNF ( Elemam et al., 2021 ). NK cells play crucial roles in fungi clearance in various ways, including cytokine production (IFN-γ, GM-CSF, and TNF-α) and the secretion of cytotoxic molecules secretion (perforin, granzymes, and granulysin) ( Elemam et al., 2021 ).…”

“…ILC1s drive type 1 immune responses which respond to intracellular pathogenic bacteria and fungi with the secretion of IFN-γ and TNF ( Elemam et al., 2021 ). NK cells play crucial roles in fungi clearance in various ways, including cytokine production (IFN-γ, GM-CSF, and TNF-α) and the secretion of cytotoxic molecules secretion (perforin, granzymes, and granulysin) ( Elemam et al., 2021 ). Granulysin participates in interference with oxidative metabolism and the energy generation of fungi, and it can also directly kill extracellular pathogens by altering the membrane integrity, while further decreasing the viability of intracellular pathogens when combined with perforin ( Elemam et al., 2021 ).…”

“…NK cells play crucial roles in fungi clearance in various ways, including cytokine production (IFN-γ, GM-CSF, and TNF-α) and the secretion of cytotoxic molecules secretion (perforin, granzymes, and granulysin) ( Elemam et al., 2021 ). Granulysin participates in interference with oxidative metabolism and the energy generation of fungi, and it can also directly kill extracellular pathogens by altering the membrane integrity, while further decreasing the viability of intracellular pathogens when combined with perforin ( Elemam et al., 2021 ). ILC2s mediate type 2 immune responses producing Th2 cytokines, including IL-4, IL-5, and IL-13 ( Elemam et al., 2021 ).…”

“…Granulysin participates in interference with oxidative metabolism and the energy generation of fungi, and it can also directly kill extracellular pathogens by altering the membrane integrity, while further decreasing the viability of intracellular pathogens when combined with perforin ( Elemam et al., 2021 ). ILC2s mediate type 2 immune responses producing Th2 cytokines, including IL-4, IL-5, and IL-13 ( Elemam et al., 2021 ). ILC3s are found to act as equivalents of Th17 cells, and mainly maintain the microbiota-host homeostasis of intestinal immunity ( Elemam et al., 2021 ).…”