Type I interferon signaling is required for the APOBEC3/Rfv3-dependent neutralizing antibody response but not innate retrovirus restriction

Barrett, Bradley S.; Harper, Michael S.; Jones, Sean T.; Guo, Kejun; Heilman, Karl J.; Kedl, Ross M.; Hasenkrug, Kim J.; Santiago, Mario L.

doi:10.1186/s12977-017-0349-2

Cited by 6 publications

(10 citation statements)

References 52 publications

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“…These observations suggest that IFN-α plays a role in enhancing and regulating antibody affinity, and they correlate with studies that highlighted the important role of mTORC1 in the antibody response 17,18,54 . In addition, studies have shown that IFN-α enhances B-cell class switching 24 , and promotes a neutralizing antibody response against virus infection 55 . Reduced IFN-α expression via decreased mTORC1 signalling in individuals with T2DM who were prescribed metformin may lead to reduced selection of germinal centres and affinity maturation.…”

Section: Discussionmentioning

confidence: 99%

Metformin-induced suppression of IFN-α via mTORC1 signalling following seasonal vaccination is associated with impaired antibody responses in type 2 diabetes

Saenwongsa

Nithichanon

Chittaganpitch

et al. 2020

Sci Rep

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Diabetes mellitus (DM) patients are at an increased risk of complications following influenza-virus infection, seasonal vaccination (SV) is recommended. However, SV with trivalent influenza vaccine (TIV) can induce antibody and type-I interferon (IFN) responses, and the effect of anti-DM treatment on these responses is incompletely understood. We evaluated the antibody response and IFN-α expression in individuals with and without type 2 DM (T2DM) following SV, and examined the effects on anti-DM treatment. TIV elicited sero-protection in all groups, but antibody persistency was <8 months, except for the antibody response to B-antigens in non-DM. T2DM impaired the IgG avidity index, and T2DM showed a significantly decreased response against H1N1 and H3N2, in addition to delaying and reducing haemagglutination-inhibition persistency against influenza B-antigens in DM groups treated with metformin (Met-DM) or glibenclamide (GB-DM). Following TIV, the Met-DM and GB-DM groups exhibited reduced IFN-α expression upon stimulation with whole-and split-virion influenza vaccines. Suppression of IFN-α expression in the Met-DM group was associated with a reduction in the mechanistic target of rapamycin complex-1 pathway and impaired IgG avidity index. Thus, single-dose TIV each year might not be suitable for T2DM. Our data could aid the development of an efficacious influenza vaccine for T2DM. The prevalence of type-2 diabetes mellitus (T2DM) is increasing worldwide, particularly in developing countries. In 2017, it was estimated that 451 million people worldwide were living with DM, and this number is expected to increase to 693 million by 2045 1. Due to multiple impairments of the immune system, patients with DM are more susceptible to infections such as influenza virus infection 2,3. Annual influenza vaccination is recommended by the World Health Organization (WHO) and the Advisory Committee on Immunization Practices in the USA to prevent influenza infection 4. The efficacy of vaccination should be evaluated in patients with T2DM, who are classified as a high-risk group for influenza infection 2,5,6. Interestingly, it has been reported that anti-DM medications further impair immune responses 7-10. Metforminthe first-line anti-hyperglycaemic drug for T2DM in Thailand-has been reported to impair the immune response by upregulating the expression of 5′ adenosine monophosphate-activated protein kinases (AMPKs) and inhibiting the mechanistic target of rapamycin (mTOR)-mediated pathway 11,12. Glibenclamide is another anti-hyperglycaemic agent that has been reported to impair immune responses by decreasing the production of interleukin (IL)-1β and IL-8 and decreasing glutathione levels in polymorphonuclear cells 13. Furthermore,

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Section: Discussionmentioning

confidence: 99%

Metformin-induced suppression of IFN-α via mTORC1 signalling following seasonal vaccination is associated with impaired antibody responses in type 2 diabetes

Saenwongsa

Nithichanon

Chittaganpitch

et al. 2020

Sci Rep

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“…Type I interferons induce the expression of interferon-stimulated genes, including STAT1/2, SOCS and A3s. IFNα induces A3s through the type I IFN receptor and activation of PKC and STAT1, and inhibition of PKC prevents the induction of A3B in breast cells ( 37–42 , 48 , 49 ). IFNα treatment is used in treating chronic hepatitis B and recent cell culture studies have shown that induction of A3 and BER by IFNα treatment is essential for decreasing hepatitis B virus ( 39 , 50–52 ).…”

Section: Discussionmentioning

confidence: 99%

APOBEC3 enzymes mediate efficacy of cisplatin and are epistatic with base excision repair and mismatch repair in platinum response

et al. 2020

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Identifying the mechanisms mediating cisplatin response is essential for improving patient response. Previous research has identified base excision repair (BER) and mismatch repair (MMR) activity in sensitizing cells to cisplatin. Cisplatin forms DNA adducts including interstrand cross-links (ICLs) that distort the DNA helix, forcing adjacent cytosines to become extrahelical. These extrahelical cytosines provide a substrate for cytosine deaminases. Herein, we show that APOBEC3 (A3) enzymes are capable of deaminating the extrahelical cytosines to uracils and sensitizing breast cancer cells to cisplatin. Knockdown of A3s results in resistance to cisplatin and induction of A3 expression in cells with low A3 expression increases sensitivity to cisplatin. We show that the actions of A3s are epistatic with BER and MMR. We propose that A3-induced cytosine deamination to uracil at cisplatin ICLs results in repair of uracils by BER, which blocks ICL DNA repair and enhances cisplatin efficacy and improves breast cancer outcomes.

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“…Thus, mA3 acted as the major effector molecule of exogenously-administered IFNα therapy. Interestingly, in an IFNAR KO background, mA3 still reduced early infectious viremia, though not via antibody-mediated mechanisms (Barrett et al 2017). Furthermore, this reduction of infectious viremia occurred in the presence or absence of LDV.…”

Section: Apobec3mentioning

confidence: 99%

“…This is not surprising, since murine retroviruses seem to suppress endogenous IFN I production, minimizing IFN signaling during acute infection (Lin et al 2014). However, in an mA3 deficient background, the loss of IFNAR increased acute FV viremia (Barrett et al 2017). These findings suggest that the low amount of virus-induced type I IFN triggered antiviral effectors other than mA3 that contributed to inhibiting acute FV replication in vivo.…”

Section: Apobec3mentioning

confidence: 99%

“…A prominent example of the effects of LDV is that Rfv3-mediated promotion of virus-neutralizing antibodies turned out to be highly dependent on the presence of LDV in the stock. LDV is a potent inducer of type I interferons (IFN I) via TLR7 signaling (Ammann et al 2009), and Apobec3 (Rfv3)mediated antibody effects are dependent on type I IFN signaling and observable only in the presence of LDV (Barrett et al 2017).…”

Section: Friend Virus Introduction and Backgroundmentioning

confidence: 99%

See 1 more Smart Citation

Friend retrovirus studies reveal complex interactions between intrinsic, innate and adaptive immunity

Dittmer

Sutter

Kassiotis

et al. 2019

FEMS Microbiology Reviews

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Approximately 4.4% of the human genome is comprised of endogenous retroviral sequences, a record of an evolutionary battle between man and retroviruses. Much of what we know about viral immunity comes from studies using mouse models. Experiments using the Friend virus (FV) model have been particularly informative in defining highly complex anti-retroviral mechanisms of the intrinsic, innate and adaptive arms of immunity. FV studies have unraveled fundamental principles about how the immune system controls both acute and chronic viral infections. They led to a more complete understanding of retroviral immunity that begins with cellular sensing, production of type I interferons, and the induction of intrinsic restriction factors. Novel mechanisms have been revealed, which demonstrate that these earliest responses affect not only virus replication, but also subsequent innate and adaptive immunity. This review on FV immunity not only surveys the complex host responses to a retroviral infection from acute infection to chronicity, but also highlights the many feedback mechanisms that regulate and counter-regulate the various arms of the immune system. In addition, the discovery of molecular mechanisms of immunity in this model have led to therapeutic interventions with implications for HIV cure and vaccine development.

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Type I interferon signaling is required for the APOBEC3/Rfv3-dependent neutralizing antibody response but not innate retrovirus restriction

Cited by 6 publications

References 52 publications

Metformin-induced suppression of IFN-α via mTORC1 signalling following seasonal vaccination is associated with impaired antibody responses in type 2 diabetes

Metformin-induced suppression of IFN-α via mTORC1 signalling following seasonal vaccination is associated with impaired antibody responses in type 2 diabetes

APOBEC3 enzymes mediate efficacy of cisplatin and are epistatic with base excision repair and mismatch repair in platinum response

Friend retrovirus studies reveal complex interactions between intrinsic, innate and adaptive immunity

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