Reduced vitamin D-induced cathelicidin production and killing of Mycobacterium tuberculosis in macrophages from a patient with a non-functional vitamin D receptor: A case report

Abstract

Tuberculosis (TB) presents a serious health problem with approximately a quarter of the world’s population infected with Mycobacterium tuberculosis (M. tuberculosis) in an asymptomatic latent state of which 5–10% develops active TB at some point in their lives. The antimicrobial protein cathelicidin has broad antimicrobial activity towards viruses and bacteria including M. tuberculosis. Vitamin D increases the expression of cathelicidin in many cell types including macrophages, and it has been suggested that the vitamin D-mediated antimicrobial activity against M. tuberculosis is dependent on the induction of cathelicidin. However, unraveling the immunoregulatory effects of vitamin D in humans is hampered by the lack of suitable experimental models. We have previously described a family in which members suffer from hereditary vitamin D-resistant rickets (HVDRR). The family carry a mutation in the DNA-binding domain of the vitamin D receptor (VDR). This mutation leads to a non-functional VDR, meaning that vitamin D cannot exert its effect in family members homozygous for the mutation. Studies of HVDRR patients open unique possibilities to gain insight in the immunoregulatory roles of vitamin D in humans. Here we describe the impaired ability of macrophages to produce cathelicidin in a HVDRR patient, who in her adolescence suffered from extrapulmonary TB. The present case is a rare experiment of nature, which illustrates the importance of vitamin D in the pathophysiology of combating M. tuberculosis.

Vitamin D and SARS‐CoV‐2

“…21 Yet, the role of vitamin D in immune regulation is complex as vitamin D triggers an up-regulated production of IL-1β. 19,22 Importantly, the effects of vitamin D on APCs indirectly skew T cell differentiation towards an anti-inflammatory phenotype. Additionally, vitamin D has a direct effect on T cells.…”

“…In macrophages, vitamin D plays a crucial antimicrobial role, as it controls the production of the central antimicrobial peptide, cathelicidin. 10,13,18,19 Additionally, vitamin D can induce a tolerogenic state in antigen presenting cells (APC). 20 This is in part due to a decreased expression of class II major histocompatibility complex (MHC II), tolllike receptor (TLR) molecules and an inhibition of TNFα, IL-6 and IL-12 secretion.…”

“…Many immune cells express the VDR. In macrophages, vitamin D plays a crucial antimicrobial role, as it controls the production of the central antimicrobial peptide, cathelicidin 10,13,18,19 . Additionally, vitamin D can induce a tolerogenic state in antigen presenting cells (APC) 20 .…”

“…This is in part due to a decreased expression of class II major histocompatibility complex (MHC II), toll‐like receptor (TLR) molecules and an inhibition of TNF‐α, IL‐6 and IL‐12 secretion 21 . Yet, the role of vitamin D in immune regulation is complex as vitamin D triggers an up‐regulated production of IL‐1β 19,22 . Importantly, the effects of vitamin D on APCs indirectly skew T cell differentiation towards an anti‐inflammatory phenotype.…”

Vitamin D in Cutaneous T-Cell Lymphoma

“…In this way, 1,25(OH) 2 D plays an important role in the immune system’s defense against bacteria and in particular mycobacteria [ 40 , 53 , 58 ]. In support, patients with genetic defects in the VDR have a compromised cathelicidin response and increased susceptibility to infection with Mycobacterium tuberculosis and other mycobacteria [ 53 , 59 ]. 1,25(OH) 2 D has recently been ascribed a role in COVID-19 infections, but the clinical importance remains controversial [ 60 ].…”