The Role of NS1 Protein in the Diagnosis of Flavivirus Infections

Abstract

Nonstructural protein 1 (NS1) is a glycoprotein among the flavivirus genus. It is found in both membrane-associated and soluble secreted forms, has an essential role in viral replication, and modulates the host immune response. NS1 is secreted from infected cells within hours after viral infection, and thus immunodetection of NS1 can be used for early serum diagnosis of dengue fever infections instead of real-time (RT)-PCR. This method is fast, simple, and affordable, and its availability could provide an easy point-of-care testing solution for developing countries. Early studies show that detecting NS1 in cerebrospinal fluid (CSF) samples is possible and can improve the surveillance of patients with dengue-associated neurological diseases. NS1 can be detected postmortem in tissue specimens. It can also be identified using noninvasive methods in urine, saliva, and dried blood spots, extending the availability and effective detection period. Recently, an enzyme-linked immunosorbent assay (ELISA) assay for detecting antibodies directed against Zika virus NS1 has been developed and used for diagnosing Zika infection. This NS1-based assay was significantly more specific than envelope protein-based assays, suggesting that similar assays might be more specific for other flaviviruses as well. This review summarizes the knowledge on flaviviruses’ NS1’s potential role in antigen and antibody diagnosis.

NS1-Specific Antibody Response Facilitates the Identification of Children With Dengue and Zika in Hyperendemic Areas

“…The added NS1 detection improved the diagnosis of DENV infection in 28% of children, similar to prior reports 7 and supporting the importance of this marker as a key for diagnosis. 38 Thus, the simultaneous detection of viremia and antigenemia is important for the early diagnostic evaluation of DENV infection, especially in hyperendemic areas.…”

Cross-Reactive Antibodies to the NS1 Protein of Omsk Hemorrhagic Fever Virus Are Absent in the Sera of Patients with Tick-Borne Encephalitis

“…For the detection of OHFV, as for other flaviviruses, the use of RT-PCR based methods are limited due to the peculiarities of the OHFV life cycle in the human body [5]. In this regard, the diagnosis of OHFV is currently based on clinical features and the presence of cross-reactivity between antibodies against the glycoprotein E of TBEV and OHFV excludes the use of existing serologic kits for differential diagnosis of these infections [6,7]. An additional difficulty for the differential diagnosis of OHF and TBE is the possibility of hemorrhagic forms of TBE, which have been described previously [8].…”

“…It is known that the most suitable target for differential serologic diagnosis of flavivirus infections is the non-structural flavivirus protein NS1 [6,9,10]. NS1 is a highly conserved protein with a molecular mass of approximately 46 kDa, which is detected in the serum of flavivirus-infected persons [6,9,11].…”

“…It is known that the most suitable target for differential serologic diagnosis of flavivirus infections is the non-structural flavivirus protein NS1 [6,9,10]. NS1 is a highly conserved protein with a molecular mass of approximately 46 kDa, which is detected in the serum of flavivirus-infected persons [6,9,11]. Initially, NS1 protein is synthesized intracellularly in a monomeric form; then, it forms a dimeric form upon maturation in the endoplasmic reticulum and is transported to the surface of infected cells [12].…”

“…The intracellular form of NS1 plays a role in viral genome replication and virion maturation, whereas the extracellular hexameric form is capable of triggering various immunologic responses, including the formation of anti-NS1 antibodies [13]. In recent years, NS1 protein has been used as an antigen for early diagnosis of mosquito-borne flavivirus infections by ELISA, as it is detected in infected individuals on day 6-8 [6,9,10]. Both antibodies to this protein and the antigen itself in the serum of an infected person may appear earlier than the immune response to protein E [14].…”