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
Fatima A. H. Al-Jaberi, C. Crone, Thomas Lindenstrøm, Nicolai Skovbjerg Arildsen, Emilia Sæderup Lindeløv, Louise Aagaard, Eva Gravesen, Rasmus Mortensen, Åse Bengård Andersen, Klaus Ølgaard, Jessica Xin Hjaltelin, Søren Brunak, Charlotte M. Bonefeld, Martin Kongsbak‐Wismann, Carsten Geisler
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 .