scholarly journals Hepatocytes trap and silence coxsackieviruses, protecting against systemic disease in mice

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Taishi Kimura ◽  
Claudia T. Flynn ◽  
J. Lindsay Whitton
Keyword(s):  
Viral Infections ◽  
Systemic Disease ◽  
Innate Immune ◽  
Type B ◽  
Wild Type ◽  
Hepatocyte Damage ◽  
Early Rise ◽  
Adenovirus Receptor ◽  
Microbial Agents ◽  
Specific Deletion

Abstract Previous research suggests that hepatocytes catabolize chemical toxins but do not remove microbial agents, which are filtered out by other liver cells (Kupffer cells and endothelial cells). Here we show that, contrary to current understanding, hepatocytes trap and rapidly silence type B coxsackieviruses (CVBs). In genetically wildtype mice, this activity causes hepatocyte damage, which is alleviated in mice carrying a hepatocyte-specific deletion of the coxsackievirus-adenovirus receptor. However, in these mutant mice, there is a dramatic early rise in blood-borne virus, followed by accelerated systemic disease and increased mortality. Thus, wild type hepatocytes act similarly to a sponge for CVBs, protecting against systemic illness at the expense of their own survival. We speculate that hepatocytes may play a similar role in other viral infections as well, thereby explaining why hepatocytes have evolved their remarkable regenerative capacity. Our data also suggest that, in addition to their many other functions, hepatocytes might be considered an integral part of the innate immune system.

scholarly journals Dissection of measles virus V protein in relation to its ability to block alpha/beta interferon signal transduction

2004 ◽  
Vol 85 (10) ◽  
pp. 2991-2999 ◽  
Author(s):  
Shinji Ohno ◽  
Nobuyuki Ono ◽  
Makoto Takeda ◽  
Kaoru Takeuchi ◽  
Yusuke Yanagi
Keyword(s):  
Immune Responses ◽  
Measles Virus ◽  
Viral Infections ◽  
Terminal Region ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Wild Type ◽  
Antagonist Activity ◽  
V Protein ◽  
P Protein

Interferon (IFN)-α and -β are the main cytokines for innate immune responses against viral infections. To replicate efficiently in the hosts, viruses have evolved various countermeasures to the IFN response. The V protein of measles virus (MV) has been shown to block IFN-α/β signalling. Here, the wild-type IC-B strain of MV was shown to grow comparably in the presence and absence of IFN-α, whereas replication of the Edmonston tag strain recovered from cloned DNA was strongly suppressed in its presence. The V protein of the IC-B strain, but not the Edmonston tag strain, blocked IFN-α signalling. The V protein of the Edmonston strain from the ATCC also inhibited IFN-α signalling. There were three amino acid differences between the V proteins of the Edmonston ATCC and tag strains, and substitutions of both residues at positions 110 and 272 were required for the Edmonston ATCC V protein to lose IFN-antagonist activity. The P protein of the IC-B strain, which shares the N-terminal 231 aa residues with the V protein, also inhibited IFN-α signalling. Indeed, fragments comprising only those 231 residues of the IC-B and Edmonston ATCC V proteins, but not the Edmonston tag V protein, were able to block IFN-α signalling. However, the N-terminal region of the Edmonston tag V protein, when attached to the C-terminal region of the Edmonston ATCC V protein, inhibited IFN-α signalling. Taken together, our results indicate that both the N- and C-terminal regions contribute to the IFN-antagonist activity of the MV V protein.

scholarly journals Dependence on Autophagy for Autoreactive Memory B Cells in the Development of Pristane-Induced Lupus

2021 ◽  
Vol 12 ◽  
Author(s):  
Albert Jang ◽  
Robert Sharp ◽  
Jeffrey M. Wang ◽  
Yin Feng ◽  
Jin Wang ◽  
...  
Keyword(s):  
B Cells ◽  
Viral Infections ◽  
Pulmonary Inflammation ◽  
Significant Loss ◽  
Memory B Cells ◽  
Wild Type ◽  
Autoantibody Production ◽  
Specific Memory ◽  
Humoral Autoimmunity ◽  
Specific Deletion

The production of autoantibodies by autoreactive B cells plays a major role in the pathogenesis of lupus. Increases in memory B cells have been observed in human lupus patients and autoimmune lpr mice. Autophagy is required for the maintenance of memory B cells against viral infections; however, whether autophagy regulates the persistence of autoantigen-specific memory B cells and the development of lupus remains to be determined. Here we show that memory B cells specific for autoantigens can be detected in autoimmune lpr mice and a pristane-induced lupus mouse model. Interestingly, B cell-specific deletion of Atg7 led to significant loss of autoreactive memory B cells and reduced autoantibody production in pristane-treated mice. Autophagy deficiency also attenuated the development of autoimmune glomerulonephritis and pulmonary inflammation after pristane treatment. Adoptive transfer of wild type autoreactive memory B cells restored autoantibody production in Atg7-deficient recipients. These data suggest that autophagy is important for the persistence of autoreactive memory B cells in mediating autoantibody responses. Our results suggest that autophagy could be targeted to suppress autoreactive memory B cells and ameliorate humoral autoimmunity.

scholarly journals The L1-dependant and Pol III transcribed Alu retrotransposon, from its discovery to innate immunity

2021 ◽  
Vol 48 (3) ◽  
pp. 2775-2789
Author(s):  
Ludwig Stenz
Keyword(s):  
Human Genome ◽  
Viral Infections ◽  
De Novo ◽  
Current Knowledge ◽  
Innate Immune ◽  
De Novo Mutation ◽  
Neuronal Diversity ◽  
Alu Sequences ◽  
Pol Iii ◽  
The Brain

AbstractThe 300 bp dimeric repeats digestible by AluI were discovered in 1979. Since then, Alu were involved in the most fundamental epigenetic mechanisms, namely reprogramming, pluripotency, imprinting and mosaicism. These Alu encode a family of retrotransposons transcribed by the RNA Pol III machinery, notably when the cytosines that constitute their sequences are de-methylated. Then, Alu hijack the functions of ORF2 encoded by another transposons named L1 during reverse transcription and integration into new sites. That mechanism functions as a complex genetic parasite able to copy-paste Alu sequences. Doing that, Alu have modified even the size of the human genome, as well as of other primate genomes, during 65 million years of co-evolution. Actually, one germline retro-transposition still occurs each 20 births. Thus, Alu continue to modify our human genome nowadays and were implicated in de novo mutation causing diseases including deletions, duplications and rearrangements. Most recently, retrotransposons were found to trigger neuronal diversity by inducing mosaicism in the brain. Finally, boosted during viral infections, Alu clearly interact with the innate immune system. The purpose of that review is to give a condensed overview of all these major findings that concern the fascinating physiology of Alu from their discovery up to the current knowledge.

scholarly journals A reassessment of the role of B7-1 expression in tumor rejection.

1995 ◽  
Vol 182 (5) ◽  
pp. 1415-1421 ◽  
Author(s):  
T C Wu ◽  
A Y Huang ◽  
E M Jaffee ◽  
H I Levitsky ◽  
D M Pardoll
Keyword(s):  
T Cells ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Tumor Rejection ◽  
Type B ◽  
Wild Type ◽  
Systemic Immunity ◽  
Murine Tumor

Introduction of the B7-1 gene into murine tumor cells can result in rejection of the B7-1 transductants and, in some cases, systemic immunity to subsequent challenge with the nontransduced tumor cells. These effects have been largely attributed to the function of B7-1 as a costimulator in directly activating tumor specific, major histocompatibility class I-restricted CD8+ T cells. We examined the role of B7-1 expression in the direct rejection as well as in the induction of systemic immunity to a nonimmunogenic murine tumor. B-16 melanoma cells with high levels of B7-1 expression did not grow in C57BL/6 recipient mice, while wild-type B-16 cells and cells with low B7-1 expression grew progressively within 21 d. In mixing experiments with B7-1hi and wild-type B-16 cells, tumors grew out in vivo even when a minority of cells were B7-1-. Furthermore, the occasional tumors that grew out after injection of 100% B-16 B7-1hi cells showed markedly decreased B7-1 expression. In vivo antibody depletions showed that NK1.1 and CD8+ T cells, but not CD4+ T cells, were essential for the in vivo rejection of tumors. Animals that rejected B-16 B7-1hi tumors did not develop enhanced systemic immunity against challenge with wild-type B-16 cells. These results suggest that a major role of B7-1 expression by tumors is to mediate direct recognition and killing by natural killer cells. With an intrinsically nonimmunogenic tumor, this direct killing does not lead to enhanced systemic immunity.

scholarly journals MyD88-Dependent Signaling Affects the Development of Meningococcal Sepsis by Nonlipooligosaccharide Ligands

2006 ◽  
Vol 74 (6) ◽  
pp. 3538-3546 ◽  
Author(s):  
Laura Plant ◽  
Hong Wan ◽  
Ann-Beth Jonsson
Keyword(s):  
Inflammatory Responses ◽  
Innate Immune ◽  
Meningococcal Sepsis ◽  
Wild Type ◽  
Microbial Infections ◽  
In The Wild ◽  
Myeloid Differentiation Factor ◽  
Dependent Pathway ◽  
Meningococcal Strain

ABSTRACT The Toll-like receptors (TLRs) and the adaptor myeloid differentiation factor 88 (MyD88) are important in the innate immune defenses of the host to microbial infections. Meningococcal ligands signaling via TLRs control inflammatory responses, and stimulation can result in fulminant meningococcal sepsis. In this study, we show that the responses to nonlipooligosaccharide (non-LOS) ligands of meningococci are MyD88 dependent. An isogenic LOS-deficient mutant of the serogroup C meningococcal strain FAM20 caused fatal disease in wild type C57BL/6 mice that was not observed in MyD88−/− mice. Fatality correlated with high proinflammatory cytokine and C5a levels in serum, high neutrophil numbers in blood, and increased bacteremia at 24 h postinfection in the wild-type mice. Infection with the parent strain FAM20 resulted in fatality in 100% of the wild-type mice and 50% of the MyD88−/− mice. We conclude that both LOS and another neisserial ligand cause meningococcal sepsis in an in vivo mouse model and confirm that meningococcal LOS can act via both the MyD88- dependent and -independent pathways, while the non-LOS meningococcal ligand(s) acts only via the MyD88-dependent pathway.

scholarly journals Directed attenuation to enhance vaccine immunity

2021 ◽  
Vol 17 (2) ◽  
pp. e1008602
Author(s):  
Rustom Antia ◽  
Hasan Ahmed ◽  
James J. Bull
Keyword(s):  
Immune Response ◽  
Genetic Engineering ◽  
Adaptive Immunity ◽  
Immune Evasion ◽  
Viral Infections ◽  
Wild Type Virus ◽  
Type Virus ◽  
Wild Type ◽  
Innate And Adaptive Immunity ◽  
Live Attenuated Vaccines

Many viral infections can be prevented by immunizing with live, attenuated vaccines. Early methods of attenuation were hit-and-miss, now much improved by genetic engineering. However, even current methods operate on the principle of genetic harm, reducing the virus’s ability to grow. Reduced viral growth has the undesired side-effect of reducing the host immune response below that of infection with wild-type. Might some methods of attenuation instead lead to an increased immune response? We use mathematical models of the dynamics of virus with innate and adaptive immunity to explore the tradeoff between attenuation of virus pathology and immunity. We find that modification of some virus immune-evasion pathways can indeed reduce pathology yet enhance immunity. Thus, attenuated vaccines can, in principle, be directed to be safe yet create better immunity than is elicited by the wild-type virus.

Sign in / Sign up

Export Citation Format

Share Document