<em>Candida</em> and Host Determinants of Susceptibility to Invasive Candidiasis

<em>Candida</em> and Host Determinants of Susceptibility to Invasive Candidiasi

The principal cell surface pattern recognition receptors involved in <i>Candida</i> recognition.

<p>The Toll-like receptor 2 (TLR2) and TLR4 recognize phospholipomannans and <i>O</i>-linked mannans, respectively, whereas TLR9 within the cytosol recognizes fungal DNA, and intracellular TLR7 (not depicted) recognizes fungal RNA. TLR2 forms heterodimers with TLR1 or TLR6 for downstream signaling (not depicted), whereas TLR4 forms homodimers. Galectin-3, together with TLR2, recognizes β-mannosides. The membrane-bound C-type lectins dendritic cell–specific ICAM3-grabbing non-integrin (DC-SIGN), macrophage-inducible C-type lectin (Mincle), and macrophage mannose receptor (MR) recognize mannose-rich <i>Candida</i> structures. In addition, dectin-1 recognizes β-glucans, and dectin 2, together with the Fcγ receptor (FcγR), recognizes mannans. The complement receptor 3 (CR3) on neutrophils also recognizes β-glucans. Moreover, the NOD-like receptor NLRP3 (nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3) forms an inflammasome complex with ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) and caspase 1, which leads to interleukin-1β (IL-1β) production. In addition, downstream dectin-1 signaling through caspase recruitment domain-containing protein 9 (CARD9) leads to non-canonical inflammasome activation and IL-1β production via caspase 8. IFNs, interferons; NF-κB, nuclear factor-κB; Syk, spleen tyrosine kinase; IRF3, interferon regulatory factor 3; TRIF, TIR-domain-containing adapter-inducing interferon-β; MyD88, myeloid differentiation primary response gene 88; BCL-10, B-cell lymphoma/leukemia 10; MALT1, mucosa-associated lymphoid tissue lymphoma translocation protein 1; TRAF6, TNF receptor–associated factor 6; IRAK, interleukin-1 receptor-associated kinase.</p

Bacterial- and viral-induced inflammation are characterized by differential plasma levels of CRP and ferritin.

<p>(<b>A</b>) Mean or median concentrations of circulating CRP and ferritin in various viral and bacterial infections illustrate that viral infections are generally characterized by high plasma ferritin with concomitant low circulating CRP [<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005973#ppat.1005973.ref018" target="_blank">18</a>, <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005973#ppat.1005973.ref045" target="_blank">45</a>, <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005973#ppat.1005973.ref047" target="_blank">47</a>, <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005973#ppat.1005973.ref054" target="_blank">54</a>, <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005973#ppat.1005973.ref057" target="_blank">57</a>, <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005973#ppat.1005973.ref091" target="_blank">91</a>–<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005973#ppat.1005973.ref094" target="_blank">94</a>], while bacterial infections are commonly characterized by high plasma CRP levels [<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005973#ppat.1005973.ref095" target="_blank">95</a>–<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005973#ppat.1005973.ref100" target="_blank">100</a>]. (<b>B</b>) Proposed model in which the induction of IL-1β/IL-6 in response to bacterial infections contributes to elevated plasma levels of CRP, while viral infections are characterized by an IL-18 response, culminating in hyperferritinemia. Importantly, IL-1/IL-6/CRP and IL-18/ferritin do not fully reflect the bacterial-viral infection dichotomy, as various bacterial infections are known to elevate plasma IL-18 levels while some viral infections are known to raise plasma IL-1β levels [<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005973#ppat.1005973.ref072" target="_blank">72</a>, <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005973#ppat.1005973.ref073" target="_blank">73</a>]. The direct correlation between circulating concentrations of IL-18 and ferritin has not yet been investigated and should be assessed in future studies. HCV: hepatitis C virus infection; EBV: Epstein-Barr virus infection; HIV: human immunodeficiency virus infection.</p

Changes in plasma cytokine concentrations during infections.

<p>Changes in plasma cytokine concentrations during infections.</p

Demographic characteristics.

<p>BMI: body mass index. Data are presented as median and interquartile range. p-values calculated using Mann-Whitney U-tests.</p><p>Demographic characteristics.</p

Experimental design of the study.

<p>The primary outcome measure was the TNF-α secretion by <i>ex vivo</i> lipopolysaccharide (LPS) -stimulated peripheral blood mononuclear cells (PBMC's). Secondary endpoints were the production of other cytokines (TNF-α, IL-6, IL-10, IL-1β, IL-17, IL-22, Interferon (IFN)-γ) by leukocytes <i>ex vivo</i> stimulated with various stimuli, β-glucan plasma levels, and Microbicidal activity of PBMC's.</p

Effect of oral β-glucan on <i>ex vivo</i> TNF-α production by PBMCs stimulated for 24 hours with lipopolysaccharide (LPS), Pam3Cys, Poly(I:C), S. <i>aureus,</i> C. <i>albicans</i>, or M. <i>tuberculosis</i> (MTB).

<p>To correct for possible baseline differences between groups, concentrations at day 0 are set at 1, and concentrations at subsequent time-points are plotted as ratios (median and interquartile range). Baseline (day 0) TNF-α concentrations in pg/ml [interquartile range] of subjects in the β-glucan and control groups were: LPS: 691 [276–2649] and 749 [287–1160]), Pam3Cys: 855 [590–1727] and 1242 [622–3567], Poly(I:C): 107 [78–399] and 125 [78–250], S. <i>aureus:</i> 21948 [14347–41751] and 19424 [12140–31722], C. <i>albicans:</i> 10875 [5860–14159] and 6208 [3924–14943], and MTB: 424 [285–1980] and 1153 [218–2461]. P values between groups were calculated using repeated measures two-way analysis of variance (ANOVA, interaction term) on log transformed data.</p

Cytokine production by M0 and M2 macrophages stimulated in varying concentrations of glucose.

<p>(A) Adherent monocytes were differentiated in either 5 or 25 mmol/L glucose into M0 macrophages (serum only) or M2 macrophages (M-CSF and serum) for 6 days and stimulated with RPMI, H37Rv lysate (1 μg/mL) or LPS (10 ng/mL). (B) Cell culture supernatants were collected and the pro-inflammatory cytokines TNF-α and IL-6 were measured along with the anti-inflammatory cytokines IL-10 and IL-1RA (n = 23). Data are shown as mean ± SEM, *p<0.05, **p<0.01 &, ***p<0.001.</p