Innate immunity to adenovirus: lessons from mice

Abstract

Adenovirus is a highly evolutionary successful pathogen, as it is widely prevalent across the animal kingdom, infecting hosts ranging from lizards and frogs to dolphins, birds, and humans. Although natural adenovirus infections in humans rarely cause severe pathology, intravenous injection of high doses of adenovirus-based vectors triggers rapid activation of the innate immune system, leading to cytokine storm syndrome, disseminated intravascular coagulation, thrombocytopenia, and hepatotoxicity, which individually or in combination may cause morbidity and mortality. Much of the information on exactly how adenovirus activates the innate immune system has been gathered from mouse experimental systems. Intravenous administration of adenovirus to mice revealed mechanistic insights into cellular and molecular components of the innate immunity that detect adenovirus particles, activate pro-inflammatory signaling pathways and cytokine production, sequester adenovirus particles from the bloodstream, and eliminate adenovirus-infected cells. Collectively, this information greatly improved our understanding of mechanisms of activation of innate immunity to adenovirus and may pave the way for designing safer adenovirus-based vectors for therapy of genetic and acquired human diseases.Human adenovirus (HAdv) is remarkably efficient at infecting and replicating in human cells. These properties made HAdv-based vectors an attractive platform for developing novel therapeutics to combat genetic diseases and cancer. Unfortunately, early studies revealed that HAdv is a potent activator of the innate and adaptive arms of the immune system, and administration to animals or patients of high doses of HAdv-based vectors, especially via an intravascular route, leads to severe immunopathology, manifested by cytokine storm syndrome, disseminated intravascular coagulation, thrombocytopenia, and hepatotoxicity, which may lead to morbidity and even mortality. To harness the full potential of HAdv as a gene delivery or oncolytic virus platform, a complete understanding of the molecular and cellular components of innate Abbreviations is a founder, shareholder, and chief scientific officer of AdCure Bio, LLC, which develops Ad-based therapies for clinical use.

The fiber knob protein of human adenovirus type 49 mediates highly efficient and promiscuous infection of cancer cell lines using a novel cell entry mechanism

“…DLD-1 colorectal cancer cells were efficiently transduced by both HAdV-C5 and HAdV-C5/D49K vectors, at 5.0x10 6 and 6.0x10 6 RLU/mg respectively. This is the only cell line where no significant difference in infectivity was observed.…”

“…However, efficacy in these applications can be hampered by pre-existing immunity against the therapeutic vector in the population resulting from prior exposure to the wild type pathogen. Such pre-existing immunity is likely to reduce the therapeutic index of such systems, due to rapid and efficient removal of the engineered therapeutic agent by the reticuloendothelial system (6,7). This is especially relevant where the therapeutic is based on the most commonly studied species C adenovirus, human adenovirus type 5 (HAdV-C5), where neutralising antibodies are found in ~90% of patients from sub-Saharan Africa and ~30% of a Scottish patient cohort (8,9).…”

Adenoviral strategies to overcome innate cellular responses to infection

“…Ad-induced IL-1b release is dependent upon endosomal DNA sensor toll-like receptor 9 (TLR9) sensing of the Ad genome [4]. Many studies in this area have been conducted using mice and mouse cells (see review by Atasheva et al [5] in this issue). In mice, Ad infection induces high levels of type I interferons (IFNs) by plasmacytoid dendritic cells (pDCs), conventional DCs, and macrophages.…”

“…The Ad DNAcore protein VII complex is transported through the nuclear pore complex, and VII proteins are released from viral genome by early gene transcription (4). E1A is the first viral protein expressed (5) during Ad infection and induces the expression of other early genes that facilitate viral replication and counteract cellular responses to infection (6). After replication occurs (7), the major late promoter is activated to produce late proteins, which are required for the formation of empty procapsids (8).…”

The superior role of coagulation factor FX over FVII in adenoviral-mediated innate immune induction of the hepatocyte: an in vitro experiment

“…Adenovirus is an effective oncolytic virus and delivery vector with appealing characteristics which made it more popular for cancer gene therapy [ 2 ]. A major obstacle for efficient viral-based gene therapy and virus replication in the target tissue is the heavy induction of innate immunity, especially when employed systemically [ 1 , 3 ]. Apart from the toxic inflammation and cytokine storm-related shock, adenovirus-mediated innate immunity is capable of mounting the adaptive immunity which could memorize the events later on.…”