Genetic Regulation of Cytokine Response in Patients with Acute Community-Acquired Pneumonia

Background: Community-acquired pneumonia (CAP) is an acute disease condition with a high risk of rapid deteriorations. We analysed the influence of genetics on cytokine regulation to obtain a better understanding of patient’s heterogeneity. Methods: For up to N = 389 genotyped participants of the PRO-GRESS study of hospitalised CAP patients, we performed a genome-wide association study of ten cytokines IL-1β, IL-6, IL-8, IL-10, IL-12, MCP-1 (MCAF), MIP-1α (CCL3), VEGF, VCAM-1, and ICAM-1. Consecutive secondary analyses were performed to identify independent hits and corresponding causal variants. Results: 102 SNPs from 14 loci showed genome-wide significant associations with five of the cytokines. The most interesting associations were found at 6p21.1 for VEGF (p = 1.58 × 10−20), at 17q21.32 (p = 1.51 × 10−9) and at 10p12.1 (p = 2.76 × 10−9) for IL-1β, at 10p13 for MIP-1α (CCL3) (p = 2.28 × 10−9), and at 9q34.12 for IL-10 (p = 4.52 × 10−8). Functionally plausible genes could be assigned to the majority of loci including genes involved in cytokine secretion, granulocyte function, and cilial kinetics. Conclusion: This is the first context-specific genetic association study of blood cytokine concentrations in CAP patients revealing numerous biologically plausible candidate genes. Two of the loci were also associated with atherosclerosis with probable common or consecutive pathomechanisms.

Variation in Parasitoid Virulence of Tetrastichus brontispae during the Targeting of Two Host Beetles

In host-parasitoid interactions, antagonistic relationship drives parasitoids to vary in virulence in facing different hosts, which makes these systems excellent models for stress-induced evolutionary studies. Venom compositions varied between two strains of Tetrastichus brontispae, Tb-Bl and Tb-On. Tb-Bl targets Brontispa longissima pupae as hosts, and Tb-On is a sub-population of Tb-Bl, which has been experimentally adapted to a new host, Octodonta nipae. Aiming to examine variation in parasitoid virulence of the two strains toward two hosts, we used reciprocal injection experiments to compare effect of venom/ovarian fluids from the two strains on cytotoxicity, inhibition of immunity and fat body lysis of the two hosts. We found that Tb-Onvenom was more virulent towards plasmatocyte spreading, granulocyte function and phenoloxidase activity than Tb-Blvenom. Tb-Blovary was able to suppress encapsulation and phagocytosis in both hosts; however, Tb-Onovary inhibition targeted only B. longissima. Our data suggest that the venom undergoes rapid evolution when facing different hosts, and that the wasp has good evolutionary plasticity.

Educating the Innate Immune System

The microbiome regulates the development of innate immunity G. Scott Worthen, Junjie Mei, Yuhong Liu, Ning Dai, Hitesh Deshmukh Circulating granulocytes are maintained within a fairly narrow window for each individual during homeostasis. This regulatory system is nonetheless capable of dramatic shifts during stress. The mechanisms that govern control over granulocyte number remain incompletely understood. Recent information, however, provides clues to the feedback control systems that regulate homeostatic and emergency granulopoiesis. The first clues have come from adult mice with abnormalities in granulocyte function. Defects in Leukocyte Integrins or chemokine receptors result in marked increases in circulating (?2 integrin) or bone marrow (Cxcr2) neutrophils, associated with increased circulating IL-17 and G-CSF. This result appears to be due to a functional inability to arrive at sentinel site(s) whence they are attracted by (among others) Cxcl5. Strikingly, a single infusion of normal WT neutrophils resets this feedback loop. One signal for expression of IL-17 and G-CSF appears to be the gut microbiome. Antibiotic treatment also resets the system, reducing neutrophil numbers and cytokine expression. Thus, at sentinel site(s), the supply of functional neutrophils is balanced against perceived threat from the microbiome. In neonates, exposure to commensal organisms is an immediate result of birth from a sterile environment into a dirty one. We have described postnatal granulopoiesis in murine neonates, a dramatic increase in circulating and bone marrow neutrophils, that lasts for 5-7 days. Human infants similarly have been shown to demonstrate a postnatal increase in circulating neutrophils for 72 hrs after birth. Antibiotic-exposed mouse pups fail to develop postnatal granulopoiesis, as do mice deficient in IL17ra, MyD88, TLR4, or G-CSF even if not exposed to antibiotics, indicating a pathway that requires exposure to LPS that induces IL17 and G-CSF, as in adults. In contrast to adults, however, commensal bacteria are required for host defense. Antibiotic-exposed pups are exquisitely sensitive to E. coli sepsis, which can be partially reversed by transfer of cecal contents or exogenous G-CSF. Furthermore, small quantities of LPS, fed by gavage, can also partially protect. Thus, neonates use exposure to commensal bacteria and their products to trigger the rapid expansion and functional maturation of granulocyte development, and in so doing, prepare the neonate for potential exposure to pathogens. Adults maintain this system, where it is at least partially responsible for maintenance of granulocyte homeostasis. Disclosures No relevant conflicts of interest to declare.

The Effect of Anti-Inflammatory and Antimicrobial Herbal Remedy PADMA 28 on Immunological Angiogenesis and Granulocytes Activity in Mice

PADMA 28 is a herbal multicompound remedy that originates from traditional Tibetan medicine and possesses anti-inflammatory, antioxidant, antimicrobial, angioprotecting, and wound healing properties. The aim of the present study was to evaluate the influence of this remedy on immunological angiogenesis and granulocytes metabolic activity in Balb/c mice. Mice were fed daily, for seven days, with 5.8 mg of PADMA (calculated from recommended human daily dose) or 0.085 mg (dose in the range of active doses of other herbal extracts studied by us previously).Results. Highly significant increase of newly formed blood vessels number inex vivocutaneous lymphocyte-induced angiogenesis test (LIA) after grafting of Balb/c splenocytes from both dosage groups to F1 hybrids (Balb/c × C3H); increase of blood lymphocytes and granulocytes number only in mice fed with lower dose of remedy; and significant suppression of metabolic activity (chemiluminescence test) of blood granulocytes in mice fed with higher dose of PADMA.Conclusion. PADMA 28 behaves as a good stimulator of physiological angiogenesis, but for this purpose it should be used in substantially lower doses than recommended by producers for avoiding the deterioration of granulocyte function.