Influenza C viruses of the family Orthomyx-oviridae differs from other members in its host range and pathogenicity. They are isolated almost exclusively from humans, although it has also been isolated from pigs and dogs.1 Influenza C viruses are endemic and sporadically cause mild respiratory disease. Influenza A and B viruses have a similar structure, whereas influenza C is more divergent. The enveloped virions have hexagonal structures on the surface and form long (500 microns) cordlike structures as they bud from the cell. Like the influenza A and B viruses, the core of influenza C viruses consists of a ribonucleoprotein made up of viral RNA and four proteins. The M1 protein lies just below the membrane, as in influenza A and B virions. A minor viral envelope protein is CM2, which functions as an ion channel. The major influenza C virus envelope glycoprotein is called HEF (hemagglutinin-esterase-fusion) (Figure1). Therefore the influenza virion contains 7 RNA segments and encodes 9 proteins., not 8 RNAs like influenza A and B viruses. Influenza C virus has only one spike protein, the hemagglutinin-esterase-fusion glycoprotein HEF which makes it unique. It combines the functions of Hemagglutinin (HA) and Neuraminidase (NA) and possesses receptor binding, receptor destroying and membrane fusion activities. HEF is synthesized on membrane-bound ribosomes and is subjected to a series of co- and post-translational modifications, most of them are required for proper folding and/or functioning.
The typical clinical symptoms of influenza C virus infection is a common cold–like illness with a fever that persists for 2 days and that usually is accompanied by cough and rhinorrhea. It causes only mild respiratory symptoms and is not thought to cause epidemics, according to the Centers for Disease Control and Prevention (CDC). It usually leads to inflammation of the upper respiratory tract, especially in children from two to six years of age. Clinical symptoms, such as cough, fever, malaise are typically mild. Only occasionally the virus spreads to the lower respiratory tract and causes bronchitis, bronchiectasie and broncho-pneumonia. There is no vaccine against influenza C virus. The majority of humans acquire antibodies to the virus early in life 2, which suggests that infection with this virus is common in childhood. A study reported 3 outbreaks of type C influenza during a 3-year study in a children’s home 3,4 which was associated with fever and mild upper respiratory tract (URT) symptoms along with antibody response. According to a study by Yoko et al, on comparing the medical files of influenza C virus–infected children versus influenza A virus–infected children they found that clinical symptoms associated with these viruses are similar. Though the maximum temperature was lower and the duration of fever was shorter in the influenza C virus–infected children. Influenza C virus presents the risk of severe respiratory illness requiring hospitalization in children—especially those <2 years old. They characterized the typical clinical symptoms of influenza C virus infection as being a common cold–like illness with a fever that persists for 2 days and that usually is accompanied by cough and rhinorrhea. Katagiri et al. reported that the symptoms of influenza C virus infection are characterized by fever and a long-lasting nasal discharge. Type C influenza virus has generally been considered to be a pathogen that causes only mild respiratory symptoms. Treatment largely consists of bed rest, avoidance of other persons, and hydration. Fluids should be consumed throughout the illness to prevent complications from dehydration. Acetaminophen or ibuprofen may be used to relieve fever, headache, and muscle aches. of bedrest, increased fluid consumption, cough suppressants, and antipyretics and analgesics (eg, acetaminophen, nonsteroidal anti-inflammatory drugs) for fever and myalgias. Influenza A or B virus infected patients get treated with neuraminidase inhibitor; however, it is ineffective against influenza C virus infection. The clinical diagnosis of influenza is not always easy; therefore, virological evidence is necessary for accurate diagnosis.
Unlike influenza A and B viruses, there has been no suitable cell line for isolation of influenza C virus. The previous reports on the clinical manifestations of type C influenza have resulted from occasions when the influenza C virus was isolated during surveillance of other respiratory viruses, such as influenza A and B viruses.5-7 Influenza C virus was first isolated in 1947 during an epidemic of respiratory illness 8 and due to difficulty in isolating it there have been few reports describing its clinical features. Sero-epidemiological studies have indicated wide distributed of the virus throughout the world. In one of the study, authors developed a tissue-culture method for primary-virus isolation, to obtain more information about the epidemiological characteristics of influenza C. This method is effective for routine work with a large number of specimens 9.
CM2, viral protein of Influenza virus C is an integral membrane protein that is oriented in membranes. Biochemical properties of CM2 are very similar to those of M2 10 and CM2 appears to possess proton permeability similar to M2 11 and also has a role in influenza C virus replication. CM2 is modified post-translationally by glycosylation. The effect of the post-translational modification of CM2 on its replication has been investigated using a reverse genetics approach with recombinant viruses lacking CM2 modification sites 12. Takanari et al investigated the effect of the phosphorylation of CM2 on influenza C virus using recombinant influenza C virus lacking phosphorylation. The results suggested that the phosphorylation of CM2 plays a role in influenza C virus replication 13. In a study by Yoko et al, the epitopes of nine MAbs on the 3D structure of the HE protein was evaluated. The data from the study is useful as a basis for future studies of the immunological and epidemiological characteristics of influenza C virus. Continued surveillance and antigenic analysis using the panel of characterized MAbs can be also helpful in determining the replacement of antigenic lineages or the possible emergence of a novel lineage of influenza C virus. Thus, further studies are required to reveal common and different principles of influenza virus budding that might be helpful to combat the disease.
- Youzbashi E, Marschall M, Chaloupka I, Meier-Ewert H. [Distribution of influenza C virus infection in dogs and pigs in Bavaria] Tierarztl. Prax. 1996;24:337–42.
- Motta FC, Luiz MO, Couceiro JN. Serological analysis reveals circulation of influenza C viruses, Brazil, Rev Saude Publica , 2000, vol. 34 (pg. 204-5)
- Katagiri S, Ohizumi A, Homma M. An outbreak of type C influenza in a children’s home, J Infect Dis , 1983, vol. 148 (pg. 51-6)
- Katagiri S, Ohizumi A, Ohyama S, Homma M. Follow-up study of type C influenza outbreak in a children’s home, Microbiol Immunol , 1987, vol. 31 (pg. 337-43)
- Francis TJr, Quilligan JJJr, Minuse E. Identification of another epidemic respiratory disease, Science , 1954, vol. 112 (pg. 495-7)
- Dykes AC, Cherry JD, Nolan CE. A clinical, epidemiologic, serologic, and virologic study of influenza C virus infection. Arch Intern Med.1980 ;140(10):1295-8
- Greenbaum E, Morag A, Zakay-Rones Z. Isolation of influenza C virus during an outbreak of influenza A and B viruses. J Clin Microbiol.1998 ;36(5):1441-2.
- TAYLOR RM. Studies on survival of influenza virus between epidemics and antigenic variants of the virus. Am J Public Health Nations Health.1949 ;39(2):171-8.
- Moriuchi H, Oshima T, Nishimura H, Nakamura K, Katsushima N. Human malignant melanoma cell line (HMV-II) for isolation of influenza C and parainfluenza viruses, J Clin Microbiol , 1990, vol. 28 (pg. 1147-50)
- Pekosz A, Lamb RA. The CM2 protein of influenza C virus is an oligomeric integral membrane glycoprotein structurally analogous to influenza A virus M2 and influenza B virus NB proteins. Virology, 1997; 237:439 -451 .
- Betakova T, Hay AJ. Evidence that the CM2 protein of influenza C virus can modify the pH of the exocytic pathway of transfected cells. J Gen Virol 2007; 88:2291 -2296 .
- Muraki Y, Murata T, Takashita E, Matsuzaki Y, Sugawara K, Hongo S. A mutation on influenza C virus M1 protein affects virion morphology by altering the membrane affinity of the protein. J Virol 2007; 81:8766 -8773 .
- Goto T, Shimotai Y, Matsuzaki Y, Muraki Y, Sho R, Sugawara K, Hongo S. Effect of Phosphorylation of CM2 Protein on Influenza C Virus Replication. J Virol. 2017 27;91(22).