Influence of oral lactoferrin on Mycobacterium tuberculosis induced immunopathology

Abstract

SUMMARY The ability of lactoferrin to provide protection and decrease immunopathology in infectious diseases was evaluated using an aggressive aerosol model of Mycobacterium tuberculosis (MTB) infection. C57BL/6 mice were challenged with MTB strain Erdman and treated with 0.5% bovine lactoferrin added to the drinking water starting at day 0 or day 7 post infection. Mice were sacrificed at three weeks post-challenge and evaluated for organ bacterial burden, lung histopathology, and ELISpot analysis of the lung and spleen for immune cell phenotypes. Mice given tap water alone had lung log10 colony forming units (CFUs) of 7.5 ± 0.3 at week 3 post-infection. Lung CFUs were significantly decreased in mice given lactoferrin starting the day of infection (6.4 ± 0.7), as well as in mice started therapeutically on lactoferrin at day 7 after established infection (6.5 ± 0.4). Quantitative immunohistochemistry using multispectral imaging demonstrated that lung inflammation was significantly reduced in both groups of lactoferrin treated mice, with decreased foamy macrophages, increased total lymphocytes, and increased numbers of CD4+ and CD8+ cells. ELISpot analysis showed that lactoferrin treated mice had increased numbers of CD4+ IFN-γ + and IL-17 producing cells in the lung, cells that have protective functions during MTB infection. Lactoferrin alone did not alter the proliferation of MTB in either broth or macrophage culture, but enhanced IFN- γ mediated MTB killing by macrophages in a nitric oxide dependent manner. These studies indicate that lactoferrin may be a novel therapeutic for the treatment of tuberculosis, and may be useful in infectious diseases to reduced immune-mediated tissue damage.

Lactoferrin: Balancing Ups and Downs of Inflammation Due to Microbial Infections

“…In this study, mice that received drinking water containing 0.5% bLf at Day 0 or 7 post-infection had lower Colony Forming Units (CFU) and lower inflammation in the lungs, with increased numbers of IFNγ producing T CD4 and CD8 cells and IL-17 producing lymphocytes when compared with animals vaccinated with BCG alone [114]. Noteworthy, bLf did not affect the in vitro replication of M. tuberculosis but instead enhanced the killing of bacteria by macrophages in a nitric oxide dependent way [114]. These studies using the models of pulmonary infection with M. tuberculosis suggest that Lf promotes certain up-regulation of pro-inflammatory response, while down-regulating overall tissue immunopathology.…”

Host-Directed Therapeutics for Tuberculosis: Can We Harness the Host?

“…Finally, lactoferrin is a protein contained in secretions, including milk, that binds to iron and has antimicrobial properties. Mice infected with M. tuberculosis and fed lactoferrin had lower bacterial loads and less lung pathology than M. tuberculosis-infected mice not fed lactoferrin (119).…”

Immunomodulatory effects of recombinant lactoferrin during MRSA infection

“…The concept to use LF for treatment of sepsis is not unique, given the protein’s ability to limit bacterial growth, and to suppress microbial-induced inflammation in a variety of animal models (20, 28–35). Our previous studies using bovine LF in the mouse model of MRSA challenge showed similar (modest) improvements in host survival concurrent with decreased serum cytokines (18).…”