Original articleNucleocapsid protein-specific IgM antibody responses in the disease progression of severe fever with thrombocytopenia syndrome
Introduction
As an emerging hemorrhagic fever disease identified in eastern Asia, severe fever with thrombocytopenia syndrome (SFTS) is caused by a novel phlebovirus in the Bunyaviridae family (Kim et al., 2015; Takahashi et al., 2014; Yu et al., 2011), known as SFTS virus (SFTSV). Another new phlebovirus, Heartland virus, was isolated from two patients suffering from severe febrile illness in Missouri, USA (McMullan et al., 2012), which shares high identity with SFTSV. These two newly emerged phleboviruses have, subsequently, exerted a global public threat.
SFTSV is transmitted through a tick bite (Luo et al., 2015) and human-to-human contact via blood or body fluid (Bao et al., 2011; Chen et al., 2017a). SFTS has an average of 12% case fatality rate, ranging from 6% to 30% (Yu et al., 2011). The clinical symptoms of SFTS infection are variable, ranging from asymptomatic or acute self-limited febrile condition to life-threatening illness. The typical clinical presentation is characterized by the sudden onset of fever, fatigue, gastrointestinal symptoms, leukopenia, and thrombocytopenia. Severe SFTS cases quickly develop multiple organ dysfunction (MOD) and disseminated intravascular coagulation (DIC), which might lead to fatality within 2 weeks of the disease onset (Zhang et al., 2013, 2012). Previous studies have identified a panel of risk factors associated with the fatality and severity of SFTS cases, such as old age, coagulation disturbance, and remarkable liver damage (Chen et al., 2017b; Cui et al., 2014; Ding et al., 2014; Jia et al., 2017; Zhang et al., 2012); however, the underlying immunological mechanism remains to be obscure. Although ribavirin has been proven effective in reducing the viral load of SFTSV, its usage could not decrease the case fatality ratio of SFTS patients (Liu et al., 2013; Lu et al., 2015). Currently, there is no effective treatment regimen for SFTS in clinical practice other than supportive care.
Antibodies typically play a key role in controlling viral infections, which are immune correlates contributing to the protective efficacy of many successful vaccines (Crowe, 2017). However, the role of SFTS-specific adaptive immune responses during an SFTS disease progression has to be elucidated. SFTSV-specific IgM antibody responses reportedly could be detected within an average period of 9 days, while SFTSV-specific IgG responses could only be detected within an average period of 6 weeks (Lu et al., 2015), and the neutralizing antibodies from SFTS patients could be maintained for at least 4 years (Huang et al., 2016). Nevertheless, the dynamic profile of antibody responses against specific SFTS viral proteins has not been further dissected and carefully characterized.
Nucleocapsid protein (NP), encoded by the small segment of bunyavirus, is the most conserved Phlebovirus genus. NP is abundantly present in viral particles and infected cells. The primary function of NP is to encapsidate the viral genome forming ribonucleoprotein complexes (RNPs) (Pekosz et al., 1999; Walter et al., 2011). Beyond its critical role in viral RNA protection, NP is actively involved in RNA transcription and replication, as well as in the formation of an inclusion body in the cytoplasm of virus-infected cells (Eifan and Elliott, 2009; Pekosz et al., 1999; Pinschewer et al., 2003; Walter et al., 2011). It has been shown that NP is highly immunogenic and that NP-specific antibodies are also readily detected early after infection in convalescent individuals, providing a robust basis for diagnostic detection of SFTS disease (Magurano and Nicoletti, 1999; Martin-Folgar et al., 2010). Interestingly, NP-specific antibodies without neutralizing activities have been demonstrated to protect animals from challenges with Rift Valley fever virus- (RVFV) and Hantavirus partially (Boshra et al., 2011b; Nakamura et al., 1985; Yoshimatsu et al., 1993). Whether viral infection-induced NP-specific humoral responses have any association with the clinical outcome of phlebovirus, including SFTSV infection in vivo, is rarely investigated in a real-world setting.
In the current report, we performed a prospective study on SFTS patients, including 34 survivors and 9 deceased patients. The kinetics of NP-specific IgM and IgG antibody responses during the acute infection phase was measured. Further, the clinical manifestations and the dynamic changes of clinical laboratory tests were determined to further define the clinical features among NP-specific IgM-positive versus IgM-delayed patients. The correlations between the magnitudes of NP-specific IgM responses and clinical laboratory parameters were analyzed. With such information, we carefully dissected the antibody profile of NP-specific humoral responses among fatal, severe and mild SFTS patients.
Section snippets
Human subjects
This retrospective study was performed in Nanjing Drum Tower Hospital, Nanjing, Jiangsu Province, China, from June 2016 to Oct 2018. Clinical manifestations and laboratory parameters were collected from 43 SFTS patients (9 deaths and 34 survivors). A SFTS patient was clinical defined if he or she agreed with the following criteria: (1) acute fever with body temperature of > 38 °C; (2) decline of white blood cell (WBC) and platelet count (PLT); (3) the contact history with tick bite or with the
The dynamic NP-specific IgM and IgG responses among SFTS patients
From Jan 2016 to Oct 2018, a total of 43 laboratory-confirmed SFTSV infected patients were recruited in this study. From this cohort, 34 patients (79%) were survived, and 9 patients (21%) died ( Table 1). The NP-specific IgM responses among SFTS patients were determined every other day beginning from the moment they were hospitalized. We found that NP-specific IgM responses were elicited among 27 (63%) out of 43 patients before day 10. Positive NP-specific IgM responses were further found in
Discussion
Here, for the first time, we comprehensively analyzed the humoral response profile for the most immunogenic viral proteins, NP, in SFTSV, among SFTS patients with different clinical outcomes. Additionally, we compared the clinical outcomes and the disease progressions between NP-specific IgM-positive versus IgM-delayed patients. The clinical features among NP-specific IgM-positive and IgM-delayed patients were further characterized, revealed by the clinical presentations and the dynamic
Conclusions
Our study has demonstrated that NP-specific IgM-delayed SFTS patients tend to have severe or even fatal clinical outcomes, validated by remarkably high levels of viral loads and extensively disturbed laboratory findings observed in NP-specific IgM-delayed patients. Furthermore, our data revealed that compared to mild SFTS patients, fatal or severe SFTS patients had significantly lower levels of NP-specific IgM but not NP-specific IgG responses, Gn-specific IgM, nor Gc-specific IgG. Our data
Acknowledgements
This work was supported by the National Natural Science Foundation of China [81600201 and 81672025], Nanjing Medical Science and Technique Development Foundation [QRX17141], Jiangsu Province’s Outstanding Medical Academic Leader Program [LJ201154], Jiangsu Province’s Clinical Medicine and Technology Special Program [BL2012034].
References (36)
- et al.
A DNA vaccine encoding ubiquitinated Rift Valley fever virus nucleoprotein provides consistent immunity and protects IFNAR(-/-) mice upon lethal virus challenge
Vaccine
(2011) Principles of broad and potent antiviral human antibodies: insights for vaccine design
Cell Host Microbe
(2017)- et al.
Clinical progression and predictors of death in patients with severe fever with thrombocytopenia syndrome in China
J. Clin. Virol.
(2014) - et al.
Cloning and expression of Rift Valley fever virus nucleocapsid (N) protein and evaluation of a N-protein based indirect ELISA for the detection of specific IgG and IgM antibodies in domestic ruminants
Vet. Microbiol.
(2007) - et al.
Preparation and evaluation of a recombinant Rift Valley fever virus NP for the detection of IgG and IgM antibodies in humans and animals by indirect ELISA
J. Virol. Methods
(2007) - et al.
Characterization of immunological responses in patients with severe fever with thrombocytopenia syndrome: a cohort study in China
Vaccine
(2015) - et al.
Characterization of Hantaan virus envelope glycoprotein antigenic determinants defined by monoclonal antibodies
J. Gen. Virol.
(1989) - et al.
Protective role of antigenic sites on the envelope protein of Hantaan virus defined by monoclonal antibodies
Arch. Virol.
(1992) - et al.
A family cluster of infections by a newly recognized bunyavirus in eastern China, 2007. Further evidence of person-to-person transmission
Clin. Infect. Dis.
(2011) - et al.
Rift valley fever: recent insights into pathogenesis and prevention
J. Virol.
(2011)
Risk factors associated with fatality of severe fever with thrombocytopenia syndrome: a meta-analysis
Oncotarget
Occupational severe fever with thrombocytopenia syndrome following needle-stick injury
Infect. Control Hosp. Epidemiol.
Risk factors associated with fatality of severe fever with thrombocytopenia syndrome: a meta-analysis
Oncotarget
Clinical features and factors associated with severity and fatality among patients with severe fever with thrombocytopenia syndrome Bunyavirus infection in Northeast China
PLoS One
Age is a critical risk factor for severe fever with thrombocytopenia syndrome
PLoS One
Mutational analysis of the Bunyamwera orthobunyavirus nucleocapsid protein gene
J. Virol.
Human antibody neutralizes severe Fever with thrombocytopenia syndrome virus, an emerging hemorrhagic Fever virus
Clin. Vaccine Immunol.
Neutralizing antibodies to severe fever with thrombocytopenia syndrome virus 4 years after hospitalization
China Emerg. Infect. Dis.
Cited by (0)
- 1
These authors contributed equally to this work.