J Immunol. Cutting edge: stealth influenza virus replication precedes the initiation of adaptive immunity.

[Giuseppe]

J Immunol. 2009 Sep 15;183(6):3569-73. Epub 2009 Aug 28.

Cutting edge: stealth influenza virus replication precedes the initiation of adaptive immunity.

Moltedo B, L?pez CB, Pazos M, Becker MI, Hermesh T, Moran TM. - Department of Microbiology and Immunology Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.

A timely immune response is crucial for the effective control of virus infection. The influenza virus NS1 protein interferes with the expression of key proinflammatory cytokines from infected cells in vitro. To investigate the effect of NS1 during the onset of immunity in vivo, we systematically studied the early events that occur in the lungs and draining lymph nodes upon infection with influenza virus. Strikingly, no sign of innate immunity was detected in the lungs for almost 2 days after infection until a sudden inflammatory burst, including IFNs, cytokines, and chemokines, occurred. This burst preceded the robust dendritic cell migration and T cell activation in the lymph nodes. An NS1-deficient virus triggered rapid inflammation in the lungs whereas a wild-type virus did not. Thus, we demonstrate that, in vivo, influenza virus uses the NS1 protein to replicate for almost 2 days after infection before detection by the immune system.

PMID: 19717515 [PubMed - in process]

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[AlaskaDenise]

Re: J Immunol. Cutting edge: stealth influenza virus replication precedes the initiation of adaptive immunity.

link to above:


http://www.jimmunol.org/cgi/content/abstract/183/6/3569

(pay for view article )

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[AlaskaDenise]

Re: J Immunol. Cutting edge: stealth influenza virus replication precedes the initiation of adaptive immunity.

For anyone else who was curious about what an NS1 truncated virus is, I'd suggest this link:

http://vir.sgmjournals.org/cgi/content/abstract/88/5/1403

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[Vibrant62]

Re: J Immunol. Cutting edge: stealth influenza virus replication precedes the initiation of adaptive immunity.

A question therefore. Does this mean that even individuals with pre-existing immunity are likely to harbour virus for two days before their immune responses are triggered? In other words, individuals with immunity are infected, but their immune system manages the virus before full-blown symptoms develop? If this were true, then in theory even individuals with immunity, could theoretically at least, transmit virus.

 

[AlaskaDenise]

Re: J Immunol. Cutting edge: stealth influenza virus replication precedes the initiation of adaptive immunity.

All references in the abstract refer to the innate system. The humoral system's secondary response (after gaining immunity through infection or vaccination) occurs in 1 to 3 days according to this source:

http://www.microrao.com/micronotes/pg/humoral_immunity.pdf

When does shedding start?

Another good source: http://biology.hamline.edu/bio/students/immunoFAQs/humoral

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[gsgs]

Re: J Immunol. Cutting edge: stealth influenza virus replication precedes the initiation of adaptive immunity.

what means: "cutting edge" ?

that sudden burst is maybe responsible for the sudden onset of
symptoms in influenza

with such few viruses present in the first hours it must be a local effect

maybe there are drugs to compensate for this, to initiate the innate response,
to release cytokenes etc. nevertheless when given at the right time

 

[Snowy Owl]

Re: J Immunol. Cutting edge: stealth influenza virus replication precedes the initiation of adaptive immunity.

Thank Ironorehopper and everybody for this important focus.

NS1 Protein of Influenza A Virus Inhibits the Function of Intracytoplasmic Pathogen Sensor, RIG-I

<table width="800" border="0" cellpadding="0" cellspacing="0"><tbody><tr><td width="670" valign="TOP"><nobr>Zhu Guo</nobr>, <nobr>Li-mei Chen</nobr>, <nobr>Hui Zeng</nobr>, <nobr>Jorge A. Gomez</nobr>, <nobr>Julie Plowden</nobr>, <nobr>Takashi Fujita</nobr>, <nobr>Jacqueline M. Katz</nobr>, <nobr>Ruben O. Donis</nobr> and <nobr>Suryaprakash Sambhara</nobr> [SIZE=-1] Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia; and Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University, Kyoto, Japan [/SIZE]
[SIZE=-1]Correspondence and requests for reprints should be addressed to Dr. Suryaprakash Sambhara, Centers for Disease Control and Prevention, 1600 Clifton Road, MS: G16, Atlanta, GA 30333. E-mail: ssambhara@cdc.gov<script type="text/javascript"><!-- var u = "ssambhara", d = "cdc.gov"; document.getElementById("em0").innerHTML = '<a href="mailto:' + u + '@' + d + '">' + u + '@' + d + '<\/a>'//--></script>[/SIZE]
<!-- ABS --> Retinoic acid?inducible gene I (RIG-I) has recently beenidentified as one of the key intracellular sensors of virusinfection. RIG-I binds to cytosolic double-stranded RNA andinitiates a signaling cascade that leads to the activation oftranscription factors required for expression of type I interferon(IFN-I). Previous evidence suggests that nonstructural protein1 (NS1) encoded by influenza A virus (IAV) suppresses IFN-Isecretion in virus-infected cells by an unknown mechanism. Inthe present study, we demonstrate that RIG-I is required forinduction of IFN-I in an IAV-infected human lung epithelialcell line. Knockdown of RIG-I expression by RNA interferencegreatly impairs production of IFN-

in cells infected with differentstrains of wild-type IAV. Furthermore, co-expression of IAVNS1 down-regulates production of IFN-

induced by RIG-I agonists,and ectopic expression of RIG-I inhibits the replication ofIAV. These results provide further information on the mechanismby which IAV NS1 antagonizes the host antiviral response.

<table border="1" cellpadding="10"><tbody><tr bgcolor="#e1e1e1"><td>[SIZE=+1]CLINICAL RELEVANCE[/SIZE] Our findings indicate the potential clinical utility of RIG-I?basedtherapeutic strategies to prevent and treat infections causedby seasonal and pandemic influenza viruses.
</td></tr></tbody></table>
</td></tr></tbody></table>
http://ajrcmb.atsjournals.org/cgi/content/abstract/36/3/263

 

[Snowy Owl]

Re: J Immunol. Cutting edge: stealth influenza virus replication precedes the initiation of adaptive immunity.

Thank Ironorehopper and everybody for this important focus.

NS1 Protein of Influenza A Virus Inhibits the Function of Intracytoplasmic Pathogen Sensor, RIG-I

​

<table width="800" border="0" cellpadding="0" cellspacing="0"><tbody><tr><td width="670" valign="TOP">

<nobr>Zhu Guo</nobr>, <nobr>Li-mei Chen</nobr>, <nobr>Hui Zeng</nobr>, <nobr>Jorge A. Gomez</nobr>, <nobr>Julie Plowden</nobr>, <nobr>Takashi Fujita</nobr>, <nobr>Jacqueline M. Katz</nobr>, <nobr>Ruben O. Donis</nobr> and <nobr>Suryaprakash Sambhara</nobr>

[SIZE=-1] [/SIZE]
[SIZE=-1]Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia; and Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University, Kyoto, Japan [/SIZE]
[SIZE=-1]Correspondence and requests for reprints should be addressed to Dr. Suryaprakash Sambhara, Centers for Disease Control and Prevention, 1600 Clifton Road, MS: G16, Atlanta, GA 30333. E-mail: ssambhara@cdc.gov[/SIZE]
[SIZE=-1]
<script type="text/javascript"><!-- var u = "ssambhara", d = "cdc.gov"; document.getElementById("em0").innerHTML = '<a href="mailto:' + u + '@' + d + '">' + u + '@' + d + '<\/a>'//--></script>[/SIZE]​

<!-- ABS --> Retinoic acid?inducible gene I (RIG-I) has recently beenidentified as one of the key intracellular sensors of virusinfection. RIG-I binds to cytosolic double-stranded RNA andinitiates a signaling cascade that leads to the activation oftranscription factors required for expression of type I interferon(IFN-I).



Previous evidence suggests that nonstructural protein1 (NS1) encoded by influenza A virus (IAV) suppresses IFN-Isecretion in virus-infected cells by an unknown mechanism.



Inthe present study, we demonstrate that RIG-I is required forinduction of IFN-I in an IAV-infected human lung epithelialcell line. Knockdown of RIG-I expression by RNA interferencegreatly impairs production of IFN-

in cells infected with differentstrains of wild-type IAV.



Furthermore, co-expression of IAVNS1 down-regulates production of IFN-

induced by RIG-I agonists,and ectopic expression of RIG-I inhibits the replication ofIAV.



These results provide further information on the mechanismby which IAV NS1 antagonizes the host antiviral response.

<table border="1" cellpadding="10"><tbody><tr bgcolor="#e1e1e1"><td>[SIZE=+1]CLINICAL RELEVANCE[/SIZE] Our findings indicate the potential clinical utility of RIG-I?basedtherapeutic strategies to prevent and treat infections causedby seasonal and pandemic influenza viruses.
</td></tr></tbody></table>
</td></tr></tbody></table>
http://ajrcmb.atsjournals.org/cgi/content/abstract/36/3/263

 

[Vibrant62]

Re: J Immunol. Cutting edge: stealth influenza virus replication precedes the initiation of adaptive immunity.

All references in the abstract refer to the innate system. The humoral system's secondary response (after gaining immunity through infection or vaccination) occurs in 1 to 3 days according to this source:

http://www.microrao.com/micronotes/pg/humoral_immunity.pdf

When does shedding start?

.

According to this 0.5 - 1 day post infection.

Abstract:

The dynamics of viral shedding and symptoms following influenza virus infection are key factors when considering epidemic control measures. The authors reviewed published studies describing the course of influenza virus infection in placebo-treated and untreated volunteers challenged with wild-type influenza virus. A total of 56 different studies with 1,280 healthy participants were considered. Viral shedding increased sharply between 0.5 and 1 day after challenge and consistently peaked on day 2. The duration of viral shedding averaged over 375 participants was 4.80 days (95% confidence interval: 4.31, 5.29). The frequency of symptomatic infection was 66.9% (95% confidence interval: 58.3, 74.5). Fever was observed in 37.0% of A/H1N1, 40.6% of A/H3N2 (p 0.86), and 7.5% of B infections (p 0.001). The total symptoms scores increased on day 1 and peaked on day 3. Systemic symptoms peaked on day 2. No such data exist for children or elderly subjects, but epidemiologic studies suggest that the natural history might differ. The present analysis confirms prior expert opinion on the duration of viral shedding or the frequency of asymptomatic influenza infection, extends prior knowledge on the dynamics of viral shedding and symptoms, and provides original results on the frequency of respiratory symptoms or fever.
Keywords: influenza, human; signs and symptoms; virus shedding

Time Lines of Infection and Disease in Human Influenza: A Review of Volunteer Challenge Studies


Infectivity is directly related to viral load - and one would expect a relatively low viral load in the first days of infection, dependant on the speed of replication of the virus ... so in theory at least it would seem that vaccinated contacts of patients could transmit virus on close exposure to others, even when a full blown clinically significant infection does not occur (provided they have a healthy immune response to the infection) i,e infection transmissions would be unlikely as viral loads would be low, but not impossible especially in a person with a compromised immune system.