Emergence of Leptin in Infection and Immunity: Scope and Challenges in Vaccines Formulation

Abstract

Deficiency of leptin (ob/ob) and/or desensitization of leptin signaling (db/db) and elevated expression of suppressor of cytokine signaling-3 (SOCS3) reported in obesity are also reported in a variety of pathologies including hypertriglyceridemia, insulin resistance, and malnutrition as the risk factors in host defense system. Viral infections cause the elevated SOCS3 expression, which inhibits leptin signaling. It results in immunosuppression by T-regulatory cells (Tregs). The host immunity becomes incompetent to manage pathogens' attack and invasion, which results in the accelerated infections and diminished vaccine-specific antibody response. Leptin was successfully used as mucosal vaccine adjuvant against Rhodococcus equi. Leptin induced the antibody response to Helicobacter pylori vaccination in mice. An integral leptin signaling in mucosal gut epithelial cells offered resistance against Clostridium difficile and Entameoba histolytica infections. We present in this review, the intervention of leptin in lethal diseases caused by microbial infections and propose the possible scope and challenges of leptin as an adjuvant tool in the development of effective vaccines.

Keywords: immunity; infections; leptin; malnutrition; obesity; vaccination.

Figure 1

Isoforms of the leptin receptor and ob-Rb signaling pathways. Six isoforms (Ob-Ra to Ob-Rf) of LEPR are existed, all are identical in extracellular ligand binding domains but differ in C-terminus. Out of six isoforms, only Ob-Rb encodes protein motifs involve in the activation of JAK-STAT signaling pathway. Ob-Rb has three tyrosine conserved regions (Y985, Y1077 & Y1138) in cytoplasmic domain. Later, it functions as a docking site for STAT3. Binding of leptin to ob-Rb leads to receptor homodimerization, in turn activates JAK/STAT pathways that result in the activation of c-fos. Ob-Rb also phosphorylates JAK to the activation of insulin receptor substrate-1 (IRS-1) and MAPK.

Figure 2

A possible link of differential leptin levels of altered physiological conditions with the rate of susceptibility to infections and vaccination. Adipose tissue of normal individuals produces adequate levels of leptin that offers resistance to multiple infections by maintaining the immune homeostasis. In diet-induced obesity, adipose tissue produces leptin in huge amount (hyperleptinemia) that causes desensitization of target cells for leptin signaling (leptin resistance) results in refractive T-cells response and huge expression of SOCS3, which increases susceptibility to infections and autoimmunity. In malnutrition, reduced mass of adipose tissue produces inadequate systemic leptin that cannot hold the Th1-Th2 balance and increases incidence of multiple infections. Both obesity and malnutrition causes impaired vaccination due to inefficient antibody response and T-cell priming.