Baseline iron status and presence of anaemia determine the course of systemic Salmonella infection following oral iron supplementation in mice

Abstract

Background: Iron deficiency anaemia (IDA) is a major health concern. However, preventive iron supplementation in regions with high burden of infectious diseases resulted in an increase of infection related morbidity and mortality. Methods: We fed male C57BL/6N mice with either an iron deficient or an iron adequate diet. Next, they received oral iron supplementation or placebo followed by intraperitoneal infection with Salmonella Typhimurium (S.Tm). Findings: We found that mice with IDA had a poorer clinical outcome than mice on an iron adequate diet. Interestingly, iron supplementation of IDA mice resulted in higher bacterial burden in organs and shortened survival. Increased transferrin saturation and non-transferrin bound iron in the circulation together with low expression of ferroportin facilitated the access of the pathogen to iron and promoted bacterial growth. Anaemia, independent of iron supplementation, was correlated with reduced neutrophil counts and cytotoxic T cells. With iron supplementation, anaemia additionally correlated with increased splenic levels of the cytokine IL-10, which is suggestive for a weakened immune control to S.Tm infection. Interpretation: Supplementing iron to anaemic mice worsens the clinical course of bacterial infection. This can be traced back to increased iron delivery to bacteria along with an impaired anti-microbial immune response. Our findings may have important implications for iron supplementation strategies in areas with high endemic burden of infections, putting those individuals, who potentially profit most from iron supplementation for anaemia, at the highest risk for infections. Funding: Financial support by the Christian Doppler Laboratory for Iron Metabolism and Anemia Research.

Physiology and Inflammation Driven Pathophysiology of Iron Homeostasis—Mechanistic Insights into Anemia of Inflammation and Its Treatment

“…In patients with an active infection, AI is actually a defense strategy of the body against invading microbes to restrict iron availability for pathogens also termed as "nutritional immunity" [234,235]. Therefore, treatment of AI in these patients, specifically with iron supplementation, not only promotes pathogen growth with increased virulence but also impairs the host immune response against pathogens [236][237][238][239]. There are three established therapies for the treatment of AI: iron replacement therapy, treatment with erythropoiesis-stimulating agents (ESAs) and red blood cell transfusion [2].…”

Airway Epithelial Cells Differentially Adapt Their Iron Metabolism to Infection With Klebsiella pneumoniae and Escherichia coli In Vitro

“…The quantitative real-time PCR was carried out as described elsewhere ( Hoffmann et al., 2021 ). In brief, total RNA isolation was prepared using acid guanidinium thiocyanate-phenol-chloroform extraction with peqGOLD Tri-Fast™ (Peqlab).…”

“…Protein extraction and Western blotting were performed as described previously ( Hoffmann et al., 2021 ). The following antibodies were used: a rabbit FPN antibody [1:2000; Eurogentec, custom made ( Petzer et al., 2020 )], a mouse TFR1 antibody (1:1000; Sigma Cat# SAB4300398), a rabbit FT antibody (1:500; Sigma), a rabbit NGAL antibody (1:1000 Abcam, ab63929), a rabbit NRF2 antibody (1:1000, Abcam, ab31163), and a rabbit actin antibody (1:500; Sigma Cat# A2066).…”

High Affinity Iron Acquisition Systems Facilitate but Are Not Essential for Colonization of Chickens by Salmonella Enteritidis

“…Some studies revealed that catecholate siderophore synthesis is not required to cause mouse typhoid indicating that requirement of iron during growth in extraintestinal sites might differ from the intestinal milieu in murine models ( Benjamin et al, 1985 ; Tsolis et al, 1996 ; Cunrath and Bumann, 2019 ). Oral supplementation of iron in mice with iron deficiency anemia increased the iron saturated transferrin fraction and led to overgrowth of STm in the liver and spleen ( Hoffmann et al, 2021 ). This overgrowth of STm was directly related to the ability to acquire iron mediated partly by catecholate siderophores (enterobactin, salmochelin) and FeoABC.…”

“…This overgrowth of STm was directly related to the ability to acquire iron mediated partly by catecholate siderophores (enterobactin, salmochelin) and FeoABC. Overall, data suggested the functional redundancy of the high affinity iron acquisition systems of STm in certain conditions, such as an imbalance of host’s iron homeostasis ( Hoffmann et al, 2021 ). All the evidence above suggests that there is a molecular arms race for iron between pathogens and the host which can decide the clinical outcome.…”