key: cord-0990980-2s4lypvx
authors: Giron, Leila B.; Peluso, Michael J.; Ding, Jianyi; Kenny, Grace; Zilberstein, Netanel F; Koshy, Jane; Hong, Kai Ying; Rasmussen, Heather; Miller, Greg; Bishehsari, Faraz; Balk, Robert A.; Moy, James N.; Hoh, Rebecca; Lu, Scott; Goldman, Aaron R.; Tang, Hsin-Yao; Yee, Brandon C.; Chenna, Ahmed; Winslow, John W.; Petropoulos, Christos J.; Kelly, J. Daniel; Wasse, Haimanot; Martin, Jeffrey N.; Liu, Qin; Keshavarzian, Ali; Landay, Alan; Deeks, Steven G.; Henrich, Timothy J.; Abdel-Mohsen, Mohamed
title: Markers of Fungal Translocation Are Elevated During Post-Acute Sequelae of SARS-CoV-2 Infection and Induce NF-κB Triggered Inflammation
date: 2022-04-13
journal: bioRxiv
DOI: 10.1101/2022.04.12.488051
sha: 57a5dd030f2b69940bddc5971d14d5e564a68821
doc_id: 990980
cord_uid: 2s4lypvx

Long COVID, a type of Post-Acute Sequelae of SARS CoV-2 infection (PASC), has been associated with sustained elevated levels of immune activation and inflammation. However, the pathophysiological mechanisms that drive this inflammation remain unknown. Inflammation during acute Coronavirus Disease 2019 (COVID-19) could be exacerbated by microbial translocation (from the gut and/or lung) to the blood. Whether microbial translocation contributes to inflammation during PASC is unknown. We found higher levels of fungal translocation – measured as β-glucan, a fungal cell wall polysaccharide – in the plasma of individuals experiencing PASC compared to those without PASC or SARS-CoV-2 negative controls. The higher β-glucan correlated with higher levels of markers of inflammation and elevated levels of host metabolites involved in activating N-Methyl-D-aspartate receptors (such as metabolites within the tryptophan catabolism pathway) with established neuro-toxic properties. Mechanistically, β-glucan can directly induce inflammation by binding to myeloid cells (via the Dectin-1 receptor) and activating Syk/NF-κB signaling. Using an in vitro Dectin-1/NF-κB reporter model, we found that plasma from individuals experiencing PASC induced higher NF-κB signaling compared to plasma from SARS-CoV-2 negative controls. This higher NF-κB signaling was abrogated by the Syk inhibitor Piceatannol. These data suggest a potential targetable mechanism linking fungal translocation and inflammation during PASC.

Dectin-1/NF-κB reporter model, we found that plasma from individuals experiencing PASC induced higher NF-κB signaling compared to plasma from SARS-CoV-2 negative controls. This higher NFκ B signaling was abrogated by the Syk inhibitor Piceatannol. These data suggest a potential targetable mechanism linking fungal translocation and inflammation during PASC. (1, 2) . A subset of 2 individuals also experience persistent, recurrent, or new COVID-19-attributed symptoms in the 3 months following acute infection -a condition commonly referred to as Long COVID (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) . Long 4 COVID, a type of Post-Acute Sequelae of SARS CoV-2 infection (PASC), can impact an individual's 5 overall health and quality of life (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) 20) . Recently, PASC has been associated with sustained 6 elevated levels of immune activation and inflammation (21) (22) (23) (24) . However, the pathophysiological 7 mechanisms that drive this inflammation remain unknown. Among the hypothesized drivers are pre-8 existing medical comorbidities, such as diabetes or obesity, the degree of SARS-CoV-2 viremia 9 during acute infection, latent Epstein-Barr virus reactivation, and the production of autoantibodies 10 (25-27). We have been investigating a known driver of systemic inflammation and severity during 11 other respiratory-related diseases, microbial translocation resulting from disruption in the gut-lung Acute COVID-19 has been associated with an increase in the plasma levels of zonulin, an established 24 physiological driver of tight junction permeability (44, 45) . This increased permeability enables the 25 translocation of both bacterial and fungal products to the blood. Such microbial translocation 26 correlates with increased systemic inflammation, disrupted gut-associated metabolites, and higher 27 mortality during acute COVID-19 (46) . These observations are supported with a series of recent 28 studies, using stool samples, showing that COVID-19 severity is associated with a state of gut 29 microbial dysbiosis and translocation (including fungal translocation) (47) (48) (49) (50) (51) (52) (53) (54) . Although these data 30 (46) (47) (48) (49) (50) (51) (52) (53) do not imply that gut microbial translocation is the primary trigger of inflammation during 31 COVID-19, as the clinical syndrome of COVID-19 likely embodies multiple pathophysiological 32 pathways, they are consistent with the literature indicating that microbial translocation fuels 33 inflammation and disease severity during respiratory diseases (28-31), and thus support a model in 34 which microbial translocation fuels inflammation following SARS-CoV-2 infection. However, 35

whether the translocation of microbes -bacteria or fungus -is related to inflammation during PASC 36 is unknown and is the subject of this study. 37 38 to the Rush PASC samples; Table 1 ). 48 We examined whether age (Fig. 1A) , body mass index (BMI; Fig. 1B) , self-rated overall 49 health/quality of life (QoL) score on a visual-analog scale (0-100; Fig. 1C) , gender, ethnicity, 50 hospitalization during acute COVID-19, or pre-existing co-morbidities (Fig. 1D ) differentiate PASC 51 from non-PASC groups within the 117 samples from the UCSF LIINC cohort. We found that a higher 52 BMI (P= 0.006; Fig. 1B ) and a higher rate of pre-existing hypertension (P= 0.003; Fig. 1D ) were 53 associated with the PASC phenotype. The overall health/QoL score was lower in volunteers 54 experiencing PASC than those in the non-PASC group (P< 0.0001; Fig. 1C ). Based on these 55 observations, we adjusted our subsequent analyses on the potential role of microbial translocation in 56 PASC for BMI and hypertension as potential confounders of the PASC phenotype in this subset from 57 the UCSF LIINC cohort. We also used the overall health/QoL score in our subsequent analyses 58 examining the potential impact of microbial translocation on individuals' well-being during PASC. 59 PASC is associated with elevated levels of fungal translocation independent of BMI and 60 hypertension. We first examined levels of tight junction permeability (measured as plasma levels of 61 zonulin) in the plasma of the 117 volunteers from the UCSF LIINC cohort. Zonulin is an established 62 physiological mediator of tight junction permeability in the digestive tract, where higher levels of 63 zonulin drive an increase in fungal and bacterial translocation (44, 55, 56) . We found that PASC is 64 associated with an increase in the plasma levels of zonulin compared to non-PASC ( Fig. 2A) . We 65 next examined levels of fungal translocation (measured as β -glucan, a fungal wall polysaccharide). 66

We observed higher levels of β -glucan in the plasma of volunteers with PASC than non-PASC 67 volunteers (in a manner linked to the number of persistent symptoms and regardless of whether 68 volunteers had been outpatients or hospitalized during their acute COVID-19; Fig. 2B dizziness, balance problems, neuropathy, vision problems).

β -glucan levels were higher in 77 individuals experiencing each of the three PASC symptom clusters compared to individuals who are 78 not experiencing PASC (Fig. 2F-H) . Furthermore, we investigated individuals experiencing each 79 symptom separately and found that β -glucan levels were higher in individuals suffering from certain 80 symptoms such as gastrointestinal (GI) symptoms (nausea and diarrhea) as well as vision problems, 81 sleep problems, neuropathy, and pain ( Supplementary Fig. 1) . We finally examined levels of 82 bacterial translocation (measured as lipopolysaccharide binding protein (LBP)); these levels were not 83 significantly different between the two groups, albeit a trend of higher levels of LBP in individuals 84 experiencing PASC (than non-PASC) was observed (Fig. 2I ). In addition, levels of soluble sCD14 85 and soluble sCD163 (markers of microbial-mediated myeloid inflammation) were not significantly 86 different between the two groups (P>0.05). 87

Given that we identified BMI and hypertension as potential confounders of the PASC phenotype in 88 the UCSF LIINC cohort, we examined whether levels of plasma β -glucan correlate with BMI and/or 89 hypertension. We found that individuals with hypertension tend to have higher levels of β -glucan 90 ( Fig. 2J) . We also found that higher BMI correlates with higher levels of plasma β -glucan (Fig. 2K) . 91 This is consistent with recent reports suggesting that obesity is associated with changes in the 92 intestinal mycobiome and with increases in levels of plasma β -glucan (58, 59) . As such, we used a 93 multivariate logistic regression model adjusting for BMI and hypertension and found that higher 94 levels of β -glucan (odds ratio (OR) 1.4 per every five units increase; P = 0.0048) and zonulin (OR 95 1.05 per every five units increase; P = 0.038) remain associated with the PASC phenotype 96 independently from BMI and/or hypertension (Fig. 2L) . The high levels of fungal translocation 97 during PASC were confirmed using PASC samples from the Rush PASC cohort; these PASC 98 samples were compared to samples from age and sex matched SARS-CoV-2 negative controls ( Fig.  99 2M). In the Rush cohort, the majority (74%) of individuals with PASC had β -glucan levels ≥ 40 100 pg/ml, whereas only 12% of SARS-CoV-2 negative controls had ≥ 40 pg/ml of β -glucan (Fig. 2M) . 101

Together these data suggest that PASC is associated with elevated levels of markers of tight junction 102 permeability (zonulin) and fungal translocation (β-glucan) to the blood. 103

Plasma β -glucan levels associate with markers of inflammation during PASC. It is well 104 established that β -glucan can directly induce inflammation following its binding to Dectin-1 on 105 macrophages, monocytes, and dendritic cells. This activates the NF-κB pathway and induces the 106 secretion of pro-inflammatory cytokines (60) (61) (62) . We, therefore, tested whether β -glucan levels 107 correlated with markers of inflammation, as well as number of symptoms, and overall health/QoL 108 score (Fig. 3A) . We found a positive correlation between β -glucan levels of inflammatory markers, 109

including TNFα, IL-6, and IP-10 (Fig. 3A, D-E) .

β -glucan levels also associated with and a higher 110 number of symptoms (Fig. 3A, B) and a lower overall health/QoL score (Fig. 3A, C) . The positive 111 correlations between levels of β -glucan and higher IL-6 and TNFα were confirmed in the PASC 112 samples from the Rush Cohort (Fig. 3F-G) . These data suggest a potential link between fungal 113 translocation and inflammation in individuals with PASC. 114

Plasma β -glucans from PASC patents activate the NF-κB pathway. The data described thus far 115 suggest that PASC is associated with high plasma levels of β -glucan in a manner linked to higher 116 inflammation. Although modest compared to levels observed during invasive fungal infections, the 117 levels of plasma β -glucan we observed in two cohorts of PASC ( Fig. 2-3 ) may be clinically 118 significant and with a potential to exacerbate a pro-inflammatory state, as suggested by a recent study 119 (57) . In that study (not focus on COVID-19), β -glucan levels in plasma ≥ 40 pg/ml were associated 120 with higher inflammation, fewer ventilator-free days, and worse survival in patients with acute 121 respiratory failure (57) .

β -glucans are known to induce inflammation by activating the NF-κB 122 pathway following binding to the Dectin-1 receptor (60-62). We, therefore, examined whether there is 123 a mechanistic link between the levels of β -glucans in the plasma of individuals with PASC and the 124

Dectin-1 dependent activation of the NF-κB pathway. For these experiments, we used a dectin- 1 125 receptor reporter cell line to measure β -glucan/Dectin-1 dependent NF-κB signaling. This cell line 126 stably expresses the Dectin-1 receptor and an NF-κB reporter linked to secreted alkaline phosphatase 127 (SEAP) so that dectin-1 receptor stimulation by β -glucan can be measured by quantifying SEAP 128 activity (Fig. 4A) . 129 We treated the Dectin-1 receptor reporter cells with 20µl of plasma from volunteers with PASC (a 130 subset of the Rush PASC cohort) or 20µl of plasma from SARS-CoV-2 negative controls. The plasma 131 from the PASC group induced significantly higher levels of NF-kB activation (in a Dectin-1 and β -132 glucan dependent manner) compared to the plasma from SARS-CoV-2 negative controls (Fig. 4B) . 133

This β -glucan/Dectin-1 dependent NF-κB signaling was significantly abrogated by the addition of a 134 selective inhibitor to the Syk signaling (Piceatannol) (Fig. 4B) . Finally, levels of β -glucan in the 135 plasma of those with PASC correlated with a higher ability of these plasma samples to induce β -136 glucan/Dectin-1 dependent NF-κB signaling using this reporter system (Fig. 4C) . These data suggest 137 that the levels of β -glucan in the plasma during PASC are capable of inducing immune activation in a 138 manner linked to the activation of the Dectin-1-Syk-NF-κB signaling pathway. Together, these 139 observations suggest a potential mechanism by which fungal translocation may contribute to 140 inflammation during PASC. Importantly, this inflammation can be inhibited using inhibitors to 141 dectin-1/Syk, providing a potential approach to mitigate PASC. 142

(NMDA) receptors with established neuro-toxic properties. Microbial translocation-mediated 144 inflammation can not only impact biological functions directly, but it also may impact them indirectly 145 by modulating the circulating levels of metabolites derived from interactions between gut microbiota 146 and the host. Many plasma metabolites are biologically active molecules able to regulate cellular 147 processes and immunological functions (63) . For example, inflammation-mediated tryptophan 148 catabolism has been associated with the development of several aging-and inflammation-associated 149 diseases during HIV infection (64) (65) (66) (67) (68) . Severe acute COVID-19 has been associated with a disruption 150 in the levels of several host metabolites such as the metabolites involved in the tryptophan catabolism 151 pathway and S-sulfocysteine (46, 69) . We therefore performed an untargeted metabolic analysis 152 (using LC-MS/MS) on the plasma samples from the UCSF LIINC cohort. Within the 117 plasma 153 samples, we identified 169 polar metabolites. We observed a significant (with nominal P value <0.05) 154 difference between PASC and non-PASC groups in 12 of these metabolites (six were higher in the 155 PASC compared to non-PASC group and six were lower in the PASC compared to non-PASC group: 156

Supplementary Table 1) . Untargeted metabolite enrichment analysis of these 12 PASC-associated 157 metabolites showed an enrichment of amino acids and certain amino-acid-related metabolic pathways 158 ( Fig. 5A) . 159

Among the differences between PASC and non-PASC groups were higher levels of quinolinic acid, a 160 downstream product of the tryptophan catabolism pathway, in those with PASC compared to the non-161 PASC group (Fig. 5B) . Tryptophan catabolism is commonly indicated by two ratios, the kynurenine 162 to tryptophan (K/T) ratio and the quinolinic acid to tryptophan (Q/T) ratio (70) . Although we did not 163 observe a statistically significant difference in the K/T ratio between PASC and non-PASC groups, 164 the Q/T ratio was higher in those with PASC compared to the non-PASC group (Fig. 5C) . Higher 165 levels of quinolinic acid and a higher Q/T ratio levels have been associated with adverse disease 166 outcomes during chronic HIV infection (64, 70) . Quinolinic acid is an established neurotoxin and 167 NMDA receptor agonist (71, 72) . Interestingly, other metabolites that also activate NMDA receptors 168 were elevated in the plasma of those with PASC, such as S-sulfocysteine (73) (Fig. 5D) , and L-169 glutamine (Fig. 5E) . Indeed, several of the 12 metabolites that differ between those with and without 170 PASC are involved in pathways related to the activation of NMDA receptors, as shown in the 171 diagram in Fig. 5F . Consistent with the neurotoxic ability of quinolinic acid and S-sulfocysteine, 172 higher Q/T and K/T ratios were associated with neuropathy during PASC (Supplementary Fig. 2 ) 173 and higher levels of S-sulfocysteine were associated with neurodegenerative PASC (and the other two 174 PASC phenotypes; Supplementary Fig. 3 ). S-sulfocysteine levels were also associated with 175 particular neurological symptoms during PASC, such as vision problems, fatigue, headache, and 176 dizziness (Supplementary Fig. 4) . Together, these data indicate that a metabolic signature associated 177 with PASC is compatible with increased tryptophan catabolism and accumulation of metabolites with 178 neuro-toxic properties, conferred by their ability to activate NMDA receptors. 179

Plasma metabolomic markers of PASC are associated with higher inflammation and lower 180 overall health. As bioactive molecules, plasma metabolites influence cellular processes and 181 immunological responses. Therefore, we asked whether any of the 12 dysregulated plasma 182 metabolites, as well as Q/T and K/T ratios (as markers of tryptophan catabolism), associated with 183 levels of β -glucan, number of symptoms, health score, or plasma markers of inflammation ( Fig. 6A  184 shows heat-maps focusing on the correlations between Q/T ratio, K/T ratio, and five elevated 185 metabolites; a complete list of correlations are shown in Supplementary Table 2 ). The most 186 significant associations were between Q/T ratio, quinolinic acid, or K/T ratio, and lower health score 187 (only in the PASC group but not in the non-PASC group; Fig. 6A-D) . In addition, levels of quinolinic 188 acid (and other elevated metabolites) and Q/T and K/T ratios correlated with higher levels of markers 189 of inflammation (Fig. 6A) , mainly during PASC. These data further support potential links between 190 disrupted metabolic activities, especially those related tryptophan catabolism and NMDA receptor 191 activation, and both inflammation and disease severity during PASC. PASC are sufficient to induce NF-κB activation in vitro and show that this activation is greater in 210 those with PASC than in SARS-CoV-2 negative controls. As noted above, β -glucan is a biomarker of 211 microbial translocation during chronic viral infections, such as HIV infection, and its levels correlate 212 with inflammation, immune suppression, and the development of HIV-associated co-morbidities (58, 213 74-78) . It can also directly induce inflammation following its binding to Dectin-1 (60) (61) (62) . Thus, these 214 data suggest a mechanism, Dectin-1-Syk-NF-κB signaling, by which the increased fungal 215 translocation during PASC may contribute to the observed sustained elevated levels of immune 216 activation and inflammation. However, a deeper mechanistic analysis will be needed to identify the 217 degree to which this NF-κB activation contributes to inflammation during PASC. Further analyses 218 could also investigate the possibility that myeloid cells (and other immune cells expressing Dectin-1) 219 from individuals with PASC are less resistant to β -glucan stimulation than cells from individuals 220 without PASC. Together, this deeper analysis could shed light on the causative versus consequential 221 links between fungal translocation, inflammation, and PASC. 222

Our results support the development of novel strategies to prevent or treat PASC, such as microbial-223 interaction targeted therapeutics (such as probiotics or metabolites) and/or selective small molecules. 224

For example, small molecules that enhance the epithelial barrier integrity or reduce the detrimental 225 effects of fungal translocation are available, including the zonulin receptor antagonist AT1001 226 (larazotide acetate); this antagonist decreased the severity and incidence of several inflammation-227 associated diseases in pre-clinical and clinical studies (79) (80) (81) and successfully treated a 17-month-228 old boy with SARS-CoV-2 associated multisystem inflammatory syndrome in children (MIS-C) who 229 failed anti-inflammatory therapies (82) . Also available are the Dectin-1 antagonist, Laminarin, which 230 has been used safely and successfully in mouse models of ischemic stroke (83) and colitis (84) , and 231 the Syk signaling inhibitor, Piceatannol, which was used to treat a mouse model of ischemic stroke 232 (83) . Our in vitro data suggest that Piceatannol may abrogate the β -glucan-mediated inflammation 233 during PASC. These molecules can form a foundation for designing strategies -to be tested pre-234 clinically as soon as pre-clinical models of PASC are available -to prevent PASC and its long-term 235 complications in individuals recovering from SARS-CoV-2 and/or other similar post-acute infection 236

Aging, and several aging-associating diseases, and even other chronic viral infections, have been 238 associated with a breakdown of homeostasis between the gut and its microbiome (85) (86) (87) . For 239 example, aging itself changes the composition of the gut microbiota (88) (89) (90) (91) (92) , leading to microbial 240 translocation, which triggers chronic inflammation (93) (94) (95) . Aging-associated diseases such as cancer, 241 diabetes, and Alzheimer's are associated with specific gut microbial signatures (96) (97) (98) (99) (100) (101) (102) (103) (104) (105) (106) . Chronic 242 HIV infection is associated with a state of gut microbial translocation, which is thought to be a major 243 cause of inflammation (107) (108) (109) (110) (111) (112) (113) (114) (115) . Even with antiretroviral therapy, the damage to the epithelial 244 barrier caused by HIV is never fully repaired, allowing microbial translocation and inflammation to 245 continue (116) (117) (118) and overall health status. The questionnaire was derived from several validated instruments (131, 132) as well as the US Centers for Disease Control list of COVID-19 symptoms. Importantly, a symptom must be described as new or worsened since the diagnosis of SARS-CoV-2 infection to be recorded as "present"; symptoms which existed prior to SARS-CoV-2 infection or were unchanged following infection are not counted. The utility of this instrument in measuring participants longitudinally has been described (19) .

Plasma levels of soluble CD14 (sCD14), soluble CD163 (sCD163), and LPS Binding Protein (LBP)

were quantified using DuoSet ELISA kits (R&D Systems; catalog # DY383-05, # DY1607-05, and # DY870-05, respectively). The plasma level of Zonulin was measured using an ELISA kit from MyBiosorce (catalog # MBS706368). β -D-glucan detection in plasma was performed using Limulus

Amebocyte Lysate (LAL) assay (Glucatell Kit, CapeCod; catalog # GT003). Figure 1D . Spearman's rank correlations were used in the analyses in Figures 2G, 3, and 6 . A multivariate logistic regression model adjusting for BMI and hypertension was used for each marker in the analysis in Figure 2I .

Wilcoxon signed rank tests were used in the analysis in Figure 4B 

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 QoL  score  GFAP  NFL  MCP1  IFNα  IFNγ  IL-6  IL-10  TNFα  IP-10  # of  symptoms   QoL  score  GFAP  NFL  MCP1 IFNα IFNγ  IL-6  IL-10  TNFα  IP-10  # of  symptoms   QoL  score  GFAP  NFL  MCP1  IFNα  IFNγ  IL-6  IL-10  TNFα  IP- n  116  79  82  82  82  14  76  82  82  82  81  34  37  37  37  33  37  37  37  37  61  45  45  45  45  11  43  45  45  45 n  116  79  82  82  82  14  76  82  82  82  81  34  37  37  37  33  37  37  37  37  61  45  45  45  45  11  43  45  45  45 n  116  79  82  82  82  14  76  82  82  82  81  34  37  37  37  33  37  37  37  37  61  45  45  45  45  11  43  45  45  45 n  116  79  82  82  82  14  76  82  82  82  81  34  37  37  37  33  37  37  37  37  61  45  45  45  45  11  43  45  45  45 n  116  79  82  82  82  14  76  82  82  82  81  34  37  37  37  33  37  37  37  37  61  45  45  45  45  11  43  45  45  45