key: cord-0863739-xb4ld4tr
authors: Luo, Wei; Li, Yi-Xin; Jiang, Li-Jun; Chen, Qian; Wang, Tao; Ye, Da-Wei
title: Targeting JAK-STAT Signaling to Control Cytokine Release Syndrome in COVID-19
date: 2020-06-17
journal: Trends Pharmacol Sci
DOI: 10.1016/j.tips.2020.06.007
sha: 7de2f50163d55cc2c2d85485e581585721e12185
doc_id: 863739
cord_uid: xb4ld4tr

Recent advances in the pathophysiologic understanding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has indicated that patients with severe COVID-19 might experience cytokine release syndrome (CRS), characterized by increased interleukin (IL)-6, IL-2, IL-7, IL-10, etc. Therefore, the treatment of cytokine storm has been proposed as a critical part of rescuing severe COVID-19. Several of the cytokines involved in COVID-19 employ a distinct intracellular signaling pathway mediated by Janus kinases (JAKs). JAK inhibition, therefore, presents an attractive therapeutic strategy for CRS, which is a common cause of adverse clinical outcomes in COVID-19. Below, we review the possibilities and challenges of targeting the pathway in COVID-19.

Several inflammatory cytokines that are involved in CRS and correlate with adverse clinical outcomes in COVID-19 employ a distinct intracellular signaling pathway mediated by Janus kinases (JAKs).

JAK-STAT signaling may be an excellent therapeutic target for the development of much needed therapies for COVID-19.

severe respiratory failure (SRF) and suggested that compared with typical bacterial community- 45 acquired pneumonia and sepsis, severe COVID-19 patients are admitted in a relatively good 46 clinical state but suffer from sudden deterioration of the clinical condition 7-8 days after the first 47 symptoms. The immune classification revealed that all patients with COVID-19-related SRF 48 have either immune dysregulation or MAS, both of which have overproduction of proinflammatory 49 cytokines [12] . They further revealed that increased absolute lymphocyte blood count was 50 observed in the six patients treated with the anti-IL-6R antibody, tocilizumab, which could partially 51 rescue the immune dysregulation state driven by SARS-CoV-2 [12] . These findings lead one to 52 opine that patients with COVID-19 who present with CRS-and sHLH-like serum cytokine (Table 1) . 88 Studies have shown that SARS-CoV-2 shares the same cell entry receptor, angiotensin 89 converting enzyme II (ACE2), as SARS-CoV and it binds to the ACE2 receptors to infect host 90 cells mainly through endocytic pathways ( Figure 2 ) [33] . By using artificial intelligence-derived The Janus kinases (JAKs) are a family of receptor-associated tyrosine kinases. This small family consists of JAK1, JAK2, b1:4 JAK3, and tyrosine kinase 2 (TYK2), which can transmit extracellular signals from many proinflammatory cytokines to b1:5 activate signal transducers and activators of transcription (STATs) [40] . The canonical JAK-STAT pathway is initiated upon 

improved the clinical condition in four patients with COVID-19 [35] . As baricitinib has minimal in-98 teraction with CYP enzymes (involved in drug metabolism in the body) and low plasma protein 99 binding, it may be a good candidate for combination therapy with other promising treatments, 100 such as remdesivir (an antiviral in clinical trials for COVID-19) [36] . 

108 data encourage the further evaluation of baricitinib in larger, randomized trials. As of June 11 109 2020, several clinical trials are evaluating the potential role of baracitinib in the treatment of 110 COVID-19 (Table 1) ; although it should be noted that the effect against viral endocytosis at 111 tolerated doses only applies to baricitinib. Whether other JAK inhibitors share the same effect 112 remain to be discovered.

113 Tofacitinib is an effective oral pan-JAK inhibitor that is approved for use in RA, an autoimmune 114 and inflammatory disease where cytokines play an important role in the disease pathogenesis 115 [39] . It is a specifically potent JAK3 and TYK2 inhibitor (EC50 less than 5 nM) [40] and thus can 116 effectively block IL-2, IL-4, IL-6, and IL-7 (Figure 1 ). Jacobs et al. recently reported a case of 117 SARS-CoV-2 infection in a woman with a 13-year history of ulcerative colitis, on tofacitinib. 118 Despite testing positive for SARS-CoV-2, the patient remained on the treatment of tofacitinib 119 because of improved clinical symptoms without holding therapy. Two weeks later, all symp-120 toms have been resolved without the necessity of hospitalization [41] . Although this does 121 not prove that tofacitinib contributed to the recovery from COVID-19 in this case, it shows 122 that the treatment of tofacitinib can potentially be continued in patients infected with SARS-123 CoV-2. While studies that directly show benefits of use of tofacitinib in COVID-19 are not yet 124 available, several clinical trials have been launched to investigate its potential benefits against 125 the disease (Table 1) .

126 Results of studies in clinical studies have demonstrated an important role of T helper 17 (Th17) 127 cells and IL-17 in the pathogenesis of inflammation and autoimmunity [42] . Moreover, immature 128 T helper (Th0) cells can differentiate into Th17 mainly in the presence of IL-6, a cytokine involved 129 in CRS in COVID-19 that also employs JAK2 to activate downstream signal (Figure 1) [44] , could 134 inhibit the expression of IL-17 in murine Th17 cells [45] . These findings suggest a possible role 135 for JAK2 inhibition and a potential use of JAK2 selective inhibitors, such as fedratinib, in blocking 136 Th17-associated cytokine activation in COVID-19 management.

137 Implications on Antibacterial and Antiviral Immunity 138 More than half of COVID-19 patients are currently treated with antibiotics [46] . In a retrospective 139 cohort study of inpatients with COVID-19 in Wuhan, Zhou et al. found that 15% of patients with enters cells through receptor-mediated endocytosis via interactions with receptors that include angiotensin converting enzyme II (ACE2), a cell surface protein on cells in the kidney, intestine, blood vessels, heart, and, importantly, alveolar epithelial type II cell. Baricitinib, a JAK inhibitor, can inhibit the process of receptor-mediated endocytosis and thus can be a viable therapeutic agent against COVID-19.

U N C O R R E C T E D P R O O F U N C O R R E C T E D P R O O F

What is the precise role of JAK-STAT in the dysregulated immune response in severe COVID-19?

Can we target JAKs and the molecular pathways they mediate in complex immune dysregulation, including COVID-19?

How can the efficacy and safety of currently available JAK inhibition therapies be improved? 

U N C O R R E C T E D P R O O F

Concerns regarding JAK inhibitors in treating COVID-19 have centered on the 143 increased risk of infection. The JAK-STAT signaling pathway is considered to be crucial in the sig-144 nal transduction of Type I IFNs (Figure 1), which are produced in response to bacterial infections 145 [47] and are also major players in preventing viral replication at the early stage of infection

The activation of Type II IFN (IFNγ) signaling, mediated by JAK1-JAK2 complexes, is known to 147 enhance antibacterial immunity [47] and upregulate the expression of several IFN-stimulated 148 genes that are major contributors to virus clearance

Bacterial infections, particularly urinary tract infections, were the most common 152 adverse effects reported in patients treated with ruxolitinib [53]. Data from the European 153 Medicines Agency suggested that upper respiratory tract infections were the most significant 154 side-effect (14.7%) in patients treated with baricitinib i . While the risk of infections associated 155 with JAK inhibition appears to be similar to that associated with biologic disease-modifying anti-156 rheumatic drugs [51,54], patients treated with JAK inhibitors also have a different risk of viral in-157 fections

reported two cases of COVID-19 who de-159 veloped hematologic toxicity during the ruxolitinib treatment. One patient had a soft-tissue infec

Previous results in animal 164 models of MERS-CoV infection have shown that Type I IFN administration was beneficial during 165 early but not late stages of infection. Instead, administration of exogenous Type I IFNs in later 166 stages increased the risk of lethality [57]. In line with these observations, Cameron et al. reported 167 that IFNα as well as Type II IFN (IFNγ) signaling was prominent in patients with SARS who 168 developed hypoxemia and died and low in the majority of SARS

recently reported that SARS-CoV-2 induces a limited IFN-I and -III response 171 but a strong chemotactic and inflammatory response, marked by a significantly increased 172 level of IL-6, IL-1β, IL1RA, CCL2, and CCL8. They indicated that the low IFN expression in 173 COVID-19 patients may be an antagonistic mechanism of SARS-CoV-2

Further, it is worth noting that ACE2, the putative receptor of SARS-CoV-2, is an 176 ISG expressed predominantly in human airway epithelial cells [60]. Whether the IFN-I treatment 177 would lead to the upregulation of ACE2 and potentially enhance infection in putative target cells 178 for SARS-CoV-2, or the use of JAK inhibitors targeting IFN signal transduction to reduce the 179 risk of SARS-CoV-2 infection, requires further investigation. While further work is necessary to 180 characterize the IFN responses in SARS-CoV-2 infection, these observations lead us to opine 181 that the strategy of JAK inhibition can still be used in the management of COVID-19

The point of concern can also be at least partially abrogated by use of selective JAK inhibitors

No. xx 9 186 and TYK2 (Figure 1), would be beneficial over other pan-JAK inhibitors as fedratinib would 187 not compromise Type I IFN (IFNα and IFNβ)-mediated antiviral and antibacterial immunity

Likewise, tofacitinib, the pan-JAK inhibitor that is a specifically potent JAK3 and TYK2 inhibitor 189 [40], could be more beneficial as it would not interact with the activation of Type II IFN 190 (IFNγ)-mediated antibacterial immunity

The Need to Identify Patient Cohorts Who Might Benefit from JAK Inhibitors 192 There is a significant need to identify patients who stand to benefit most from treatments with JAK 193 inhibitors, as some groups of patients might benefit more than others

JAK inhibitors should be 209 administrated with caution in COVID-19 patients with factors for thrombotic risk, such as 210 old age, immobilization, mechanical ventilation, and central venous catheter use. Also, 211 proper evaluation of the risk of venous thromboembolism risk before the use of JAK inhibi-212 tors has great importance in patients with COVID-19

suggests that inhibition of the pathway can be a therapeutic strategy for the management of 218 COVID-19. The potential role of JAK inhibitors in treating patients with COVID-19-associated 219 CRS is an area of active investigation with multiple ongoing clinical trials (Table 1)

JAK inhibi-226 tors are also known to block the activity of IL-6

IL-6, JAK inhibitors can simultaneously target actions of multiple cytokines inside 228 the cells, including IL-2, IL-4, and IFNγ (Figure 1). Moreover, the theoretical benefit of JAK inhibi-229 tion in the management of COVID-19-associated CRS would be applicable to currently available 230 FDA-approved JAK inhibitors and also extend to candidate JAK inhibitors currently in clinical trials 231 for other disease indications, that, while not yet approved by FDA

For example, 235 BMS-986165 and PF-06826647, TYK2 selective inhibitors currently in Phase II clinical trials for 236 psoriasis [70] (Clinical Trial Numbers ii : NCT03881059 and NCT03895372) (Figure 1), can be 237 tested in COVID-19. These inhibitors would potentially not interact with the Type II IFN response 238 (IFNγ) necessary in antibacterial immunity but still inhibit other cytokines in COVID-19. Similarly, 239 potential JAK3-specific inhibitors, such as decernotinib (VX-509), currently in a Phase II clinical 240 trial for RA [71] (Clinical Trial Number: NCT01590459) and ritlecitinib (PF-06651600 iii ) (Figure 1), 241 currently in a Phase III clinical trial for alopecia areata (Clinical Trial Number: NCT04006457) can 242 also be tested against COVID-19 either as monotherapy or in combination with IL-6/IL-6R 243 antagonists. These JAK inhibitors can be expected to not interact with both Type I and Type II 244 IFN-mediated antibacterial and antiviral responses

Additionally, results from ongoing clinical trials 249 (Table 1) would also be needed to confirm the optimum time and dosing regimens to administer 250 JAK inhibitors in COVID-19. Finally, the identification of alternative targeted therapeutics with 251 greater isoform selectivity, while minimizing adverse reactions, is the need of the hour. In this re-252 gard, the negative feedback loop that regulates JAK-STAT signaling via suppressor of cytokine 253 signaling (SOCS) (Box 1) may also provide novel mechanisms of action to generate new thera-254 peutics, such as SOCS mimetics or stabilizers for management of COVID-19 (see Outstanding 255 Questions) [72,73]. In summary, JAK inhibition appears to be an attractive therapeutic option to Dr Jianfeng Zhou who helped prepare and review the manuscript. This work was supported by HUST 261 COVID-19 Rapid Response Call 2020kfyXGYJ015 to Dr Tao Wang

Disclaimer Statement

Dr Jianfeng Zhou is the PI who designed a prospective, multicenter, single-blind, randomized controlled Phase II trial involving 265 patients with severe COVID-19 to evaluate the efficacy and safety of ruxolitinib. This trial is registered at www.chictr.org.cn as 266 ChiCTR-OPN-2000029580

A novel coronavirus from patients with 277 pneumonia in China

COVID-19: consider cytokine storm syn-279 dromes and immunosuppression

Clinical features of patients infected with 281 2019 novel coronavirus in Wuhan

Targeting interleukin-6 signaling in clinic

Interleukin-6: designing specific thera-321 peutics for a complex cytokine

Effective treatment of severe COVID-19 pa-327 tients with tocilizumab

Type I/II cytokines, JAKs, and new 330 strategies for treating autoimmune diseases

Ruxolitinib: the first 333 FDA approved therapy for the treatment of myelofibrosis

FDA approves Eli Lilly's baricitinib

FDA approves tofacitinib for rheumatoid ar-338 thritis

JAK inhibitors in dermatology: 342 the promise of a new drug class

Filgotinib (GLPG0634/GS-6034), 347 an oral JAK1 selective inhibitor, is effective in combination with 348 methotrexate (MTX) in patients with active rheumatoid arthritis 349 and insufficient response to MTX: results from a randomised, 350 dose-finding study (DARWIN 1)

A Phase IIb study of ABT-494

JAK-1 inhibitor, in patients with rheumatoid arthritis and an inade-354 quate response to anti-tumor necrosis factor therapy

Efficacy and safety of peficitinib 357 (ASP015K) in patients with rheumatoid arthritis and an inade-358 quate response to conventional DMARDs: a randomised, 359 double-blind

JAK inhibition with ruxolitinib versus 362 best available therapy for myelofibrosis

Ruxolitinib in adult patients with secondary 365 haemophagocytic lymphohistiocytosis: an open-label, single-366 centre, pilot trial

Ruxolitinib in treatment of severe coronavirus 368 disease 2019 (COVID-19): a multicenter, single-blind, randomized 369 controlled trial

Baricitinib as potential treatment for 375

Mechanism of baricitinib supports arti-377

Baricitinib therapy in COVID-19: A pilot 386

Development of anti-TNF therapy for rheu-389 matoid arthritis

Janus kinase (JAK) inhibitors in the treat-391

Effects of AIN457, a fully human anti-398 body to interleukin-17A, on psoriasis, rheumatoid arthritis, and 399 uveitis

Fedratinib: first approval

Clinical characteristics of coronavirus 409 disease 2019 in China

Decoding type I and III interferon signal-413

Ruxolitinib-associated infections: a sys-420 tematic review and meta-analysis

Response to ruxolitinib in patients with 426 intermediate-1-, intermediate-2-, and high-risk myelofibrosis

A systematic review and meta-analysis 429

Side effects of ruxolitinib in patients with 436

-2 infection: two case reports

Agents Published online

No. xx 444 immune responses in patients with severe acute respiratory 445 syndrome

Imbalanced host response to 447 SARS-CoV-2 drives development of COVID-19

SARS-CoV-2 receptor ACE2 is an 450 interferon-stimulated gene in human airway epithelial cells and 451 is enriched in specific cell subsets across tissues

Baricitinib: a new oral treatment for rheuma-454 toid arthritis

COVID-19: the vasculature unleashed

Coagulopathy and antiphospholipid anti-466 bodies in patients with Covid-19

Pilot prospective open

JAK inhibitors for treatment of psoria-481 sis: focus on selective TYK2 inhibitors

Decernotinib: a next-generation Jakinib

Negative regulators of JAK/STAT signaling 485 in rheumatoid arthritis and osteoarthritis

Targeting SOCS proteins to control

SOCS proteins: negative regula-489 tors of cytokine signaling