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Pyruvate is the end product of glycolysis and transported into the mitochondria for use in the tricarboxylic acid (TCA) cycle. It is also a common additive in cell culture media. We discovered that inclusion of sodium pyruvate in culture media during infection of mouse bone marrow derived macrophages with influenza A virus impaired cytokine production (IL-6, IL-1β, and TNF-α). Sodium pyruvate did not inhibit viral RNA replication. Instead, the addition of sodium pyruvate alters cellular metabolism and diminished mitochondrial reactive oxygen species (ROS) production and lowered immune signaling. Overall, sodium pyruvate affects the immune response produced by macrophages but does not inhibit virus replication., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Human Respiratory Syncytial Virus (HRSV) is an important pathogen and is associated with mortality in the young, old, and immuno-compromised. Due to the lack of effective therapeutic antivirals or a vaccine, there is a critical need for continued research in this field. Here we tested the ability of the FDA approved proteasome inhibitor bortezomib to inhibit HRSV in vitro and in vivo. We observed significant inhibition of HRSV replication in Vero cells at bortezomib concentrations from 20 to 40 ng/ml. Bortezomib was well tolerated in mice when administered intranasally at concentrations of < or = 0.3 mg/kg or intraperitoneally at 1.0 mg/kg. However, treatment of HRSV-infected mice with doses as low as 0.01 mg/kg resulted in increased pulmonary inflammation and mortality compared to mock treated-infected control animals. Examination of cytokine expression levels from lungs of bortezomib treated HRSV-infected mice revealed an increase in G-CSF, IL-6, MCP-1, and RANTES levels and a decrease in total IL-12 compared to mock treated-infected control animals. These data indicate that treatment with bortezomib during HRSV infection may alter the immune response and could potentially create a risk for patients treated with bortezomib in the event of a respiratory tract infection., (2009 Elsevier Ireland Ltd. All rights reserved.)

The ketone bodies β-hydroxybutyrate (BHB) and acetoacetate (AcAc) support mammalian survival during states of energy deficit by serving as alternative sources of ATP. BHB levels are elevated by starvation, caloric restriction, high-intensity exercise, or the low-carbohydrate ketogenic diet. Prolonged fasting reduces inflammation; however, the impact that ketones and other alternative metabolic fuels produced during energy deficits have on the innate immune response is unknown. We report that BHB, but neither AcAc nor the structurally related short-chain fatty acids butyrate and acetate, suppresses activation of the NLRP3 inflammasome in response to urate crystals, ATP and lipotoxic fatty acids. BHB did not inhibit caspase-1 activation in response to pathogens that activate the NLR family, CARD domain containing 4 (NLRC4) or absent in melanoma 2 (AIM2) inflammasome and did not affect non-canonical caspase-11, inflammasome activation. Mechanistically, BHB inhibits the NLRP3 inflammasome by preventing K(+) efflux and reducing ASC oligomerization and speck formation. The inhibitory effects of BHB on NLRP3 are not dependent on chirality or starvation-regulated mechanisms like AMP-activated protein kinase (AMPK), reactive oxygen species (ROS), autophagy or glycolytic inhibition. BHB blocks the NLRP3 inflammasome without undergoing oxidation in the TCA cycle, and independently of uncoupling protein-2 (UCP2), sirtuin-2 (SIRT2), the G protein-coupled receptor GPR109A or hydrocaboxylic acid receptor 2 (HCAR2). BHB reduces NLRP3 inflammasome-mediated interleukin (IL)-1β and IL-18 production in human monocytes. In vivo, BHB or a ketogenic diet attenuates caspase-1 activation and IL-1β secretion in mouse models of NLRP3-mediated diseases such as Muckle-Wells syndrome, familial cold autoinflammatory syndrome and urate crystal-induced peritonitis. Our findings suggest that the anti-inflammatory effects of caloric restriction or ketogenic diets may be linked to BHB-mediated inhibition of the NLRP3 inflammasome.

Influenza A virus (IAV) causes seasonal epidemics annually and pandemics every few decades. Most antiviral treatments used for IAV are only effective if administered during the first 48 h of infection and antiviral resistance is possible. Therapies that can be initiated later during IAV infection and that are less likely to elicit resistance will significantly improve treatment options. Pyruvate, a key metabolite, and an end product of glycolysis, has been studied for many uses, including its anti-inflammatory capabilities. Sodium pyruvate was recently shown by us to decrease inflammasome activation during IAV infection. Here, we investigated sodium pyruvate's effects on IAV in vivo. We found that nebulizing mice with sodium pyruvate decreased morbidity and weight loss during infection. Additionally, treated mice consumed more chow during infection, indicating improved symptoms. There were notable improvements in pro-inflammatory cytokine production (IL-1β) and lower virus titers on day 7 post-infection in mice treated with sodium pyruvate compared to control animals. As pyruvate acts on the host immune response and metabolic pathways and not directly on the virus, our data demonstrate that sodium pyruvate is a promising treatment option that is safe, effective, and unlikely to elicit antiviral resistance. [ABSTRACT FROM AUTHOR]

Infections with any pathogen can be severe and present with numerous complications caused by the pathogen or the host immune response to the invading microbe. However, coinfections, also called polymicrobial infections or secondary infections, can further exacerbate disease. Coinfections are more common than is often appreciated. In this review, we focus specifically on coinfections between viruses and other viruses, bacteria, parasites, or fungi. Importantly, innate immune signaling and innate immune cells that facilitate clearance of the initial viral infection can affect host susceptibility to coinfections. Understanding these immune imbalances may facilitate better diagnosis, prevention, and treatment of such coinfections. [ABSTRACT FROM AUTHOR]

Viral-bacterial coinfections, such as with influenza A virus and Streptococcus pneumoniae (S.p.), are known to cause severe pneumonia. It is well known that the host response has an important role in disease. Interleukin-1β (IL-1β) is an important immune signaling cytokine responsible for inflammation and has been previously shown to contribute to disease severity in numerous infections. Other studies in mice indicate that IL-1β levels are dramatically elevated during IAV-S.p. coinfection. However, the regulation of IL-1β during coinfection is unknown. Here, we report the NLRP3 inflammasome is the major inflammasome regulating IL-1β activation during coinfection. Furthermore, elevated IL-1β mRNA expression is due to enhanced TLR2-MYD88 signaling, which increases the amount of pro-IL-1β substrate for the inflammasome to process. Finally, NLRP3 and high IL-1β levels were associated with increased bacterial load in the brain. Our results show the NLRP3 inflammasome is not protective during IAV-S.p. coinfection. [ABSTRACT FROM AUTHOR]

Inflammasomes are multiprotein complexes that form in the cytoplasm in response to cellular damage and cytosolic pathogen-associated molecules during infection. These complexes play important roles in initiating innate and adaptive immune responses to infectious disease. In addition, inflammasomes are now recognized as important mediators of sterile inflammation in various autoimmune and autoinflammatory diseases. Interestingly, microbiota and infection play critical roles in the development of 'sterile inflammation'. Herein, we highlight recent advances in our understanding of the role for inflammasomes in nucleic acid-, nucleosome-, and histone-driven sterile inflammation and discuss knowledge gaps and areas of potential future research. [ABSTRACT FROM AUTHOR]

Nucleotide oligomerization and binding domain ( NOD)-like receptors ( NLRs) are a major constituent of the cytosolic innate immune-sensing machinery and participate in a wide array of pathways including nuclear factor κB ( NF-κB), mitogen-activated protein kinase ( MAPK), inflammasome, and type I interferon ( IFN) signaling. NLRs have known roles in autoimmune, autoinflammatory, and infectious diseases. With respect to virus infection, NLRP3 is the most extensively studied NLR, including mechanisms of activation and inhibition. Furthermore, the importance of NLRP3 in both innate and adaptive immunity has been demonstrated. In comparison to NLRP3, the roles of other NLRs during virus infection are only just emerging. NLRC2 is an important activator of innate antiviral signaling and was recently found to mitigate inflammation during virus infection through autophagy. Finally, functions for NLRX1 in immune modulation and reactive oxygen species production require further examination and the importance of NLRC5 as a transactivator of major histocompatibility complex ( MHC) class I and antigen presentation is currently developing. In this review, we discuss current knowledge pertaining to viruses and NLRs as well as areas of potential research, which will help advance the study of NLR biology during virus infection. [ABSTRACT FROM AUTHOR]

NOD-like receptors (NLRs) are a class of cytoplasmic pattern-recognition receptors. Although most NLRs play some role in immunity, their functions range from regulating anti gen presentation (NLRC5, CIITA) to pathogen/damage sensing (NLRP1, NLRP3, NLRC1/2, NLRC4) to suppression or modulation of inflammation (NLRC3, NLRP6, NLRP12, NLRX1). However, NLRP2, NLRP5, and NLRP7 are also involved in non-immune pathways such as embryonic development. In this review, we highlight some of the least well-understood aspects of NLRs, including the mechanisms by which they sense pathogens or damage. NLRP3 recognizes a diverse range of stimuli and numerous publications have presented potential unifying models for NLRP3 activation, but no single mechanism proposed thus far appears to account for all possible NLRP3 activators. Additionally, NLRC3, NLRP6, and NLRP12 inhibit NF-κB activation, but whether direct ligand sensing is a requirement for this function is not known. Herein, we review the various mechanisms of sensing and activa tion proposed for NLRP3 and other inflammasome activators. We also discuss the role of NLRC3, NLRP6, NLRP12, and NLRX1 as inhibitors and how they are activated and function in their roles to limit inflammation. Finally, we present an overview of the emerging roles that NLRP2, NLRP5, and NLRP7 play during embryonic development and postulate on the potential pathways involved. [ABSTRACT FROM AUTHOR]

Abstract: Human Respiratory Syncytial Virus (HRSV) is an important pathogen and is associated with mortality in the young, old, and immuno-compromised. Due to the lack of effective therapeutic antivirals or a vaccine, there is a critical need for continued research in this field. Here we tested the ability of the FDA approved proteasome inhibitor bortezomib to inhibit HRSV in vitro and in vivo. We observed significant inhibition of HRSV replication in Vero cells at bortezomib concentrations from 20 to 40ng/ml. Bortezomib was well tolerated in mice when administered intranasally at concentrations of ≤0.3mg/kg or intraperitoneally at 1.0mg/kg. However, treatment of HRSV-infected mice with doses as low as 0.01mg/kg resulted in increased pulmonary inflammation and mortality compared to mock treated-infected control animals. Examination of cytokine expression levels from lungs of bortezomib treated HRSV-infected mice revealed an increase in G-CSF, IL-6, MCP-1, and RANTES levels and a decrease in total IL-12 compared to mock treated-infected control animals. These data indicate that treatment with bortezomib during HRSV infection may alter the immune response and could potentially create a risk for patients treated with bortezomib in the event of a respiratory tract infection. [Copyright &y& Elsevier]

Keywords: NLRP3; inflammasome; inflammation; NOD-like receptor; infection; immunological diseases EN NLRP3 inflammasome inflammation NOD-like receptor infection immunological diseases 1 2 2 05/22/20 20200519 NES 200519 NOD-like Receptors (NLRs) are a large family of 22 intracellular proteins in humans. However, NLRP3-mediated signaling triggered unwanted overt inflammation resulting in kidney damage during Zika virus infection, which was associated with altered aquaporin expression in the kidney tissue. NLRP3, inflammasome, inflammation, NOD-like receptor, infection, immunological diseases. [Extracted from the article]