Increased Incidence, Morbidity, and Mortality in Human Coronavirus NL63 Associated with ACE Inhibitor Therapy and Implication in SARS-CoV-2 (COVID-19).

BACKGROUND: The endemic human coronavirus NL63 strain (HCoV-NL63) employs angiotensin-converting enzyme 2 (ACE-2) receptors on cell surfaces to infect hosts in the same manner as SARS-CoV and the novel SARS-CoV-2. It has been proposed that patients on angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin receptor blockers (ARB) therapy infected with SARS-CoV-2 have a higher mortality rate due to over-expression of ACE-2 receptors. AIM: We sought to evaluate the impact of ACE-I/ARB on infectivity of various endemic coronavirus strains, hypothesizing that rates of ACE-I use among patients with HCoV-NL63 would be higher compared to other endemic coronavirus strains that do not utilize the ACE-2 receptor. DESIGN/METHODS: A retrospective cohort study was designed to evaluate a total 466 subjects with a positive respiratory pathogens panel for one of the endemic coronavirus strains. Rate of ACE-I/ARB use among each coronavirus strain and clinical outcomes from the 88 HCoV-NL63 positive subjects was collected. RESULTS: Analysis revealed a higher rate of ACE-I (p=0.006) use among the HCoV-NL63 positives compared to the other three endemic coronavirus strains. The rate of invasive mechanical ventilation (p=0.007) and 90-day mortality (p=0.045) among HCoV-NL63 positives on ACE-I therapy was higher compared to those HCoV-NL63 positives not on ACE-I therapy. CONCLUSION: Concurrent therapy with an ACE-I was associated with an increased rate and severity of infection with the HCoV-NL63. This association was not found in infected patients on concurrent ARB therapy. These findings support the importance of further evaluation in patients on these therapies who are infected with the novel coronavirus SARS-CoV-2.

Dietary bovine lactoferrin alters mucosal and systemic immune cell responses in neonatal piglets.

Lactoferrin (LF) is a multifunctional immune protein found at high concentrations in human milk. Herein, the effect of dietary bovine LF (bLF) on mucosal and systemic immune development was investigated. Colostrum-deprived piglets were fed formula containing 130 [control (Ctrl)], 367 (LF1), or 1300 (LF3) mg of bLF/(kg body weight · d). To provide passive immunity, sow serum was provided orally during the first 36 h of life. Blood, spleen, mesenteric lymph node (MLN), and ascending colon (Asc) contents were collected on day 7 (n = 10-14/group) and day 14 (n = 10-12/group). Immune cell populations were quantified by flow cytometry and immunoglobulins (Igs) were measured by ELISA. Additionally, immune cells were isolated from spleen and MLNs (n = 7/group) on day 7 and stimulated ex vivo with phytohemagglutinin or lipopolysaccharide (LPS) ± LF for 72 h. Secreted cytokine concentrations were quantified by multiplex assay. Lymphocyte populations [cluster determinant (CD)4, CD8, and natural killer cells] developed normally and were unaffected by dietary bLF. LF3 piglets tended to have 1.4 to 2 times more serum IgG than Ctrl piglets (P = 0.07) or LF1 piglets (P = 0.03), but IgA in Asc contents was unaffected by bLF. Asc IgA was 4 times higher on day 14 than day 7. Spleen cells from LF3 piglets produced 2 times more interleukin (IL)-10 and tumor necrosis factor (TNF)-α ex vivo than those from Ctrl or LF1 piglets. MLN cells from LF1 and LF3 piglets produced 40% more IL-10 and tended to produce 40% more IL-6 (P = 0.05) than those from Ctrl piglets. However, ex vivo bLF did not affect the cytokine response of spleen or MLN cells to LPS. In summary, dietary bLF alters the capacity of MLN and spleen immune cells to respond to stimulation, supporting a role for LF in the initiation of protective immune responses in these immunologically challenged neonates.

Dietary bovine lactoferrin increases intestinal cell proliferation in neonatal piglets.

Lactoferrin is a bioactive milk protein that stimulates cell proliferation in vitro; however, limited in vivo evidence exists to allow lactoferrin to be incorporated into infant formula. Herein, the effect of dietary bovine lactoferrin (bLF) on neonatal intestinal growth and maturation was investigated guided by the hypothesis that bLF would increase cellular proliferation leading to functional differences in neonatal piglets. Colostrum-deprived piglets were fed formula containing 0.4 [control (Ctrl)], 1.0 (LF1), or 3.6 (LF3) g bLF/L for the first 7 or 14 d of life. To provide passive immunity, sow serum was provided orally during the first 36 h of life. Intestinal cell proliferation, histomorphology, mucosal DNA concentration, enzyme activity, gene expression, and fecal bLF content were measured. Intestinal enzyme activity, DNA concentration, and villus length were unaffected by bLF. However, crypt proliferation was 60% greater in LF1- and LF3-fed piglets than in Ctrl piglets, and crypt depth and area were 20% greater in LF3-fed piglets than in Ctrl piglets. Crypt cells from LF3-fed piglets had 3-fold higher ß-catenin mRNA expression than did crypt cells from Ctrl piglets. Last, feces of piglets fed bLF contained intact bLF, suggesting that some bLF was resistant to digestion and could potentially affect intestinal proliferation through direct interaction with intestinal epithelial cells. This study is the first to our knowledge to show that dietary bLF stimulates crypt cell proliferation in vivo. The increased ß-catenin expression indicates that Wnt signaling may in part mediate the stimulatory effect of bLF on intestinal cell proliferation.

Current Nutritional Therapies in Inflammatory Bowel Disease: Improving Clinical Remission Rates and Sustainability of Long-Term Dietary Therapies.

Inflammatory Bowel Disease (IBD) includes a spectrum of chronic immune-mediated intestinal diseases thought to be related to the complex interaction between the host immune system and the intestinal microbiome. Research supports the use of nutritional therapy in IBD; however, it is not routinely used in clinical practice. This literature review seeks to advance the understanding of diet and its effect in IBD with a focus on both Crohn's Disease (CD) and Ulcerative Colitis (UC). The contribution of diet to the development and treatment of IBD cannot be overstated. In both pediatric as well as adult IBD, nutritional interventions have been shown to improve clinical symptoms as well as inflammatory burden. The impact of dietary intervention is best exemplified through the use of Exclusive Enteral Nutrition (EEN) in CD. EEN and clinical research on exclusionary whole food diets-Crohn's Disease Exclusion Diet (CDED), Specific Carbohydrate Diet (SCD), low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet, and Mediterranean Diet-are discussed within this review. Current clinical literature supports the elimination of detrimental components and the incorporation of low processed whole foods in the diet. Additional prospective and longitudinal dietary studies on sustainable and long-term dietary options, along with a deeper understanding of the mechanism, are needed to further advance the role of nutritional interventions in IBD.

Dietary Bovine Lactoferrin Reduces Staphylococcus aureus in the Tissues and Modulates the Immune Response in Piglets Systemically Infected with S. aureus.

BACKGROUND: Bovine lactoferrin (bLf) reduces Staphylococcus aureus infection in premature infants and promotes the growth of Bifidobacterium infantis, a predominant infant gut species. We hypothesized that bLf in combination with B. infantis would reduce the severity of systemic S. aureus infection. OBJECTIVE: The aim was to determine the effects of oral administration of bLf and B. infantis on the course of systemic S. aureus infection. METHODS: Colostrum-deprived piglets were fed formulas containing 4 g whey/L (CON group) or bLf (LF group). One-half of the piglets in each group were gavaged with B. infantis (109 colony-forming units/d), resulting in 2 additional groups (BI or COMB, respectively). On day 7, piglets were intravenously injected with S. aureus. Blood samples were collected preinfection and every 12 h postinfection for immune analyses. Tissue samples were collected on day 12 for analysis of bacterial abundance and gene expression. RESULTS: Preinfection, LF piglets had lower serum interleukin 10 (IL-10), a higher percentage of lymphocytes, and a lower percentage of neutrophils than BI or COMB piglets. After infection, dietary bLf increased piglet weight gain, reduced staphylococcal counts in the kidneys, and tended to lower staphylococcal counts in the lungs and heart. Dietary bLf also decreased kidney IL-10 and increased lung interferon γ (IFN-γ) mRNA. B. infantis increased splenic IFN-γ expression. Renal Toll-like receptor 2 was upregulated in BI piglets but not in COMB piglets. Postinfection, BI piglets had increased serum IL-10 and decreased memory T cell populations. LF and COMB piglets had fewer circulating monocytes and B cells than CON or BI piglets. CONCLUSIONS: Dietary bLf and B. infantis produced independent and tissue-specific effects. Piglets fed bLf alone or in combination with B. infantis mounted a more effective immune response and exhibited lower bacterial abundance. This study provides biological underpinnings to the clinical benefits of bLf observed in preterm infants but does not support B. infantis administration during S. aureus infection.