BK Polyomavirus Evades Innate Immune Sensing by Disrupting the Mitochondrial Network and Promotes Mitophagy

Manzetti, Julia; Weissbach, Fabian H.; F, Graf; Unterstab, Gunhild; Wernli, Marion; Hopfer, Helmut; Drachenberg, Cinthia B.; Rinaldo, Christine Hanssen; Hirsch, Hans H.

doi:10.1016/j.isci.2020.101257

Cited by 40 publications

(29 citation statements)

References 91 publications

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“…Two recent comprehensive studies demonstrated that hRPTEC fail to sense BKPyV (90,91). This was shown to be partly dependent on the expression of the agnoprotein, a viral factor whose function has remained unclear so far (91). We demonstrated that although renal CD1c+ DC are refractory to BKPyV infection they remain able to capture virions and trans-infect hRPTEC in vitro.…”

Section: Discussionmentioning

confidence: 74%

“…Our results with human MDDC as well as freshly isolated blood and renal CD1c+ cDC confirm these observations and extend them to bona fide DC subsets supporting that such an immune ignorance towards BKPyV could exist in vivo. Two recent comprehensive studies demonstrated that hRPTEC fail to sense BKPyV (90,91). This was shown to be partly dependent on the expression of the agnoprotein, a viral factor whose function has remained unclear so far (91).…”

Section: Discussionmentioning

confidence: 99%

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Non-permissive human conventional CD1c⁺dendritic cells enabletrans-infection of human primary renal tubular epithelial cells and protect BK polyomavirus from neutralization

Sikorski

Coulon

Peltier

et al. 2020

Preprint

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The BK polyomavirus (BKPyV) is a ubiquitous human virus that persists in the renourinary epithelium. Immunosuppression can lead to BKPyV reactivation in the first year post-transplantation in kidney (KTR) and hematopoietic stem cell transplant recipients. In KTR, persistent DNAemia has been correlated to the occurrence of polyomavirus-associated nephropathy (PVAN) that can lead to graft loss if not properly controlled. Based on recent observations that conventional dendritic cells (cDC) specifically infiltrate PVAN lesions, we hypothesized that those cells could play a role in BKPyV infection. We first demonstrated that monocyte-derived DC (MDDC), an in vitro model for mDC, captured BKPyV particles through an unconventional GRAF-1 endocytic pathway. Neither BKPyV particles nor BKPyV-infected cells were shown to activate MDDC. Endocytosed virions were efficiently transmitted to permissive cells and shown to be protected from the antibody-mediated neutralization. Finally, we demonstrated that freshly isolated CD1c+ mDC from the blood and kidney parenchyma behaved similarly to MDDC thus extending our results to cells of clinical relevance. This study sheds light on a potential unprecedented CD1c+ mDC involvement in the BKPyV infection as a promoter of viral spreading.

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Non-permissive human conventional CD1c⁺dendritic cells enabletrans-infection of human primary renal tubular epithelial cells and protect BK polyomavirus from neutralization

Sikorski

Coulon

Peltier

et al. 2020

Preprint

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“…Genome replication leads to transcription of the late genes, which form the capsid to contain the nascent viral genomes and complete the virus replication cycle. Some polyomaviruses, including JCPyV and BKPyV, encode an additional late gene, the agnoprotein; recent work suggests that that agnoprotein interdicts the cell’s innate immune antiviral defenses [ 32 ]. Release of progeny PyV virions was long considered to be coincident with host cell lysis.…”

Section: The Polyomavirus Lifecyclementioning

confidence: 99%

JCPyV VP1 Mutations in Progressive Multifocal Leukoencephalopathy: Altering Tropism or Mediating Immune Evasion?

Lauver

Lukacher

2020

Viruses

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Polyomaviruses are ubiquitous human pathogens that cause lifelong, asymptomatic infections in healthy individuals. Although these viruses are restrained by an intact immune system, immunocompromised individuals are at risk for developing severe diseases driven by resurgent viral replication. In particular, loss of immune control over JC polyomavirus can lead to the development of the demyelinating brain disease progressive multifocal leukoencephalopathy (PML). Viral isolates from PML patients frequently carry point mutations in the major capsid protein, VP1, which mediates virion binding to cellular glycan receptors. Because polyomaviruses are non-enveloped, VP1 is also the target of the host’s neutralizing antibody response. Thus, VP1 mutations could affect tropism and/or recognition by polyomavirus-specific antibodies. How these mutations predispose susceptible individuals to PML and other JCPyV-associated CNS diseases remains to be fully elucidated. Here, we review the current understanding of polyomavirus capsid mutations and their effects on viral tropism, immune evasion, and virulence.

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“…After primary infection, BKPyV persists in the renourinary tract and, despite potent BKPyV-specific T-cells and neutralizing antibodies (NAbs) [ 13 ], immunocompetent healthy blood donors show low-level urinary BKPyV shedding indicating effective escape from immune control [ 16 ]. BKPyV immune escape is favored by the viral agnoprotein which actively interferes with innate immune sensing, hence preventing the timely alarming of the adaptive immune response [ 17 ]. Following transplantation, BKPyV-replication increases in rates and magnitude in the KT-recipients as a result of immunosuppression, HLA-mismatches, and preferentially involves donor-derived BKPyV genotypes [ 18 , 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Variations in BK Polyomavirus Immunodominant Large Tumor Antigen-Specific 9mer CD8 T-Cell Epitopes Predict Altered HLA-Presentation and Immune Failure

Leuzinger

Kaur

Wilhelm

et al. 2020

Viruses

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Failing BK polyomavirus (BKPyV)-specific immune control is underlying onset and duration of BKPyV-replication and disease. We focused on BKPyV-specific CD8 T-cells as key effectors and characterized immunodominant 9mer epitopes in the viral large tumor-antigen (LTag). We investigated the variation of LTag-epitopes and their predicted effects on HLA-class 1 binding and T-cell activation. Available BKPyV sequences in the NCBI-nucleotide (N = 3263), and the NCBI protein database (N = 4189) were extracted (1368 sequences) and analyzed for non-synonymous aa-exchanges in LTag. Variant 9mer-epitopes were assessed for predicted changes in HLA-A and HLA-B-binding compared to immunodominant 9mer reference. We identified 159 non-synonymous aa-exchanges in immunodominant LTag-9mer T-cell epitopes reflecting different BKPyV-genotypes as well as genotype-independent variants altering HLA-A/HLA-B-binding scores. Decreased binding scores for HLA-A/HLA-B were found in 27/159 (17%). This included the immunodominant LPLMRKAYL affecting HLA-B*07:02-, HLA-B*08:01- and HLA-B*51:01-presentation. In two healthy BKPyV-seropositive HLA-B*07:02 blood donors, variant LSLMRKAYL showed reduced CD8 T-cell responses compared to LPLMRKAYL. Thus, despite LTag being highly conserved, aa-exchanges occur in immunodominant CD8 T-cell epitopes of BKPyV-genotypes as well as of genotypes -independent variants, which may contribute to genotype-dependent and genotype-independent failure of cellular immune control over BKPyV-replication. The data warrant epidemiological and immunological investigations in carefully designed clinical studies.

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BK Polyomavirus Evades Innate Immune Sensing by Disrupting the Mitochondrial Network and Promotes Mitophagy

Cited by 40 publications

References 91 publications

Non-permissive human conventional CD1c⁺dendritic cells enabletrans-infection of human primary renal tubular epithelial cells and protect BK polyomavirus from neutralization

Non-permissive human conventional CD1c⁺dendritic cells enabletrans-infection of human primary renal tubular epithelial cells and protect BK polyomavirus from neutralization

JCPyV VP1 Mutations in Progressive Multifocal Leukoencephalopathy: Altering Tropism or Mediating Immune Evasion?

Variations in BK Polyomavirus Immunodominant Large Tumor Antigen-Specific 9mer CD8 T-Cell Epitopes Predict Altered HLA-Presentation and Immune Failure

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BK Polyomavirus Evades Innate Immune Sensing by Disrupting the Mitochondrial Network and Promotes Mitophagy

Cited by 40 publications

References 91 publications

Non-permissive human conventional CD1c+dendritic cells enabletrans-infection of human primary renal tubular epithelial cells and protect BK polyomavirus from neutralization

Non-permissive human conventional CD1c+dendritic cells enabletrans-infection of human primary renal tubular epithelial cells and protect BK polyomavirus from neutralization

JCPyV VP1 Mutations in Progressive Multifocal Leukoencephalopathy: Altering Tropism or Mediating Immune Evasion?

Variations in BK Polyomavirus Immunodominant Large Tumor Antigen-Specific 9mer CD8 T-Cell Epitopes Predict Altered HLA-Presentation and Immune Failure

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Non-permissive human conventional CD1c⁺dendritic cells enabletrans-infection of human primary renal tubular epithelial cells and protect BK polyomavirus from neutralization

Non-permissive human conventional CD1c⁺dendritic cells enabletrans-infection of human primary renal tubular epithelial cells and protect BK polyomavirus from neutralization