Abbreviations: 3-MA, 3-methyladenine; AKT, v-akt murine thymoma viral oncogene homolog; ALB, albumin; ATG7, autophagyrelated 7; CD, cluster of differentiation; CD5L, CD5 molecule-like; FCS, fetal calf serum; FSL1, pam2CGDPKHPKSF; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; IL, interleukin; MAP1LC3A/B (LC3), microtubule-associated protein 1 light chain 3 a/b; LPS, lipopolysaccharide; LTA, lipoteichoic acid; MK, macrophages; MAPK, mitogen-activated protein kinase; moAb, monoclonal antibody;; NFKB, nuclear factor of kappa light polypeptide gene enhancer in B-cells; oxLDL, oxidized low-density lipoprotein; PB monocytes, peripheral blood monocytes; PBS, phosphate-buffered saline; PI3K, phosphoinositide 3-kinase; PIK3C3, phosphatidylinositol 3-kinase, catalytic subunit type 3; poAb, polyclonal antibody; PMA, phorbol 12-myristate 13-acetate; PtdIns3K, phosphatidylinositol 3-kinase; PtdIns3P, phosphatidylinositol 3-phosphate; r-HsCD5L, recombinant human (Homo sapiens) CD5L; RELA, v-rel avian reticuloendotheliosis viral oncogene homolog A; siRNA, short interference RNA; SRCR, scavenger receptor cysteine-rich; TBS, tris-buffered saline; TLRs, toll-like receptors; TNF, tumor necrosis factor.CD5L (CD5 molecule-like) is a secreted glycoprotein that participates in host response to bacterial infection. CD5L influences the monocyte inflammatory response to the bacterial surface molecules lipopolysaccharide (LPS) and lipoteichoic acid (LTA) by inhibiting TNF secretion. Here we studied the intracellular events that lead to macrophage TNF inhibition by human CD5L. To accomplish this goal, we performed functional analyses with human monocytic THP1 macrophages, as well as with peripheral blood monocytes. Inhibition of phosphatidylinositol 3-kinase (PtdIns3K) reversed the inhibitory effect of CD5L on TNF secretion. Among the various PtdIns3K isoforms, our results indicated that CD5L activates PtdIns3K (whose catalytic subunit is termed PIK3C3), a key modulator involved in autophagy. Further analysis revealed a concomitant enhancement of autophagy markers such as cellular LC3-II content, increased LC3 puncta, as well as LC3-LysoTracker Red colocalization. Moreover, electron microscopy showed an increased presence of cytosolic autophagosomes in THP1 macrophages overexpressing CD5L. Besides preventing TNF secretion, CD5L also inhibited IL1B and enhanced IL10 secretion. This macrophage anti-inflammatory pattern of CD5L was reverted upon silencing of autophagy protein ATG7 by siRNA transfection. Additional siRNA experiments in THP1 macrophages indicated that the induction of autophagy mechanisms by CD5L was achieved through cell-surface scavenger receptor CD36, a multiligand receptor expressed in a wide variety of cell types. Our data represent the first evidence that CD36 is involved in autophagy and point to a significant contribution of the CD5L-CD36 axis to the induction of macrophage autophagy.

The administration of a high fat content diet is an accelerating factor for metabolic syndrome, impaired glucose tolerance, and early type 2 diabetes. The present study aims to assess the impact of a high fat diet on tuberculosis progression and microbiota composition in an experimental animal model using a C3HeB/FeJ mouse strain submitted to single or multiple consecutive aerosol infections. These models allowed us to study the protection induced by Bacillus Calmette-Guérin vaccination as well as by the natural immunity induced by chemotherapy after a low dose Mycobacterium tuberculosis infection. Our results show that a high fat diet is able to trigger a pro-inflammatory response, which results in a faster progression toward active tuberculosis and an impaired protective effect of BCG vaccination, which is not the case for natural immunity. This may be related to dysbiosis and a reduction in the Firmicutes/Bacteroidetes ratio in the gut microbiota caused by a decrease in the abundance of the Porphyromonadaceae family and, in particular, the Barnesiella genus. It should also be noted that a high fat diet is also related to an increase in the genera Alistipes, Parasuterella, Mucispirillum, and Akkermansia, which have previously been related to dysbiotic processes. As diabetes mellitus type 2 is a risk factor for developing tuberculosis, these findings may prove useful in the search for new prophylactic strategies for this population subset.

Tuberculosis (TB) is still responsible for the deaths of >1 million people yearly worldwide, and therefore its correct diagnosis is one of the key components of any TB eradication programme. However, current TB diagnostic tests have many limitations, and improved diagnostic accuracy is urgently needed. To improve the diagnostic performance of traditional serology, a combination of different Mycobacterium tuberculosis (MTB) antigens and different antibody isotypes has been suggested, with some showing promising performance for the diagnosis of active TB. Given the incomplete protection conferred by bacille Calmette–Guérin (BCG) vaccination against adult pulmonary TB, efforts to discover novel TB vaccines are ongoing. Efficacy studies from advanced TB vaccines designed to stimulate cell-mediated immunity failed to show protection, suggesting that they may not be sufficient and warranting the need for other types of immunity. The role of antibodies as tools for TB therapy, TB diagnosis and TB vaccine design is discussed. Finally, we propose that the inclusion of antibody-based TB vaccines in current clinical trials may be advisable to improve protection.