|Year : 2020 | Volume
| Issue : 4 | Page : 274-279
General awareness on hantavirus infection: A brief review
Department of Life Sciences, School of Environment and Life Sciences (SELS), Independent University Bangladesh (IUB), Dhaka, Bangladesh
|Date of Submission||29-Jun-2020|
|Date of Acceptance||07-Jul-2020|
|Date of Web Publication||30-Dec-2020|
Dr. Rashed Noor
Department of Life Sciences (DLS), School of Environment and Life Sciences (SELS), Independent University, Bangladesh (IUB), Plot 16, Block B, Aftabuddin Ahmed Road, Bashundhara, Dhaka 1229
Source of Support: None, Conflict of Interest: None
Hantavirus is a negative, stranded RNA virus, largely known to be transmitted to humans, especially working in forestry from the rodents. The human-to-human transmission of this virus is still in obscure; however, upon transmission of this virus from the rodent fluids, its fatality is noticed mainly through the hyperinflammatory syndrome and the cardiopulmonary syndrome. Several reports revealed an alternation of the immune response including the natural killer cells, CD8+ T cells, neutrophils, and several cytokines during the viral pathogenesis. Unlike the other emerging viruses including the currently ongoing novel coronavirus (COVID-19) pandemic, the global mortality rate due to hantavirus infection is so far very low, which, in turn, made the general people all around the world know a very little about this virus. Besides, no effective antiviral therapy including vaccines has yet been developed to combat the viral infection. Lots of comprehensive reports elaborately discussed this virus pointing toward its dreadfulness. The current review discussed the fatal effects of the hantavirus infection in a relatively simplistic way, which can be easily understood by the general community who are still unaware of the risks posed by this relatively uncommon virus.
Keywords: Hantavirus, immunity, mortality, rodents
|How to cite this article:|
Noor R. General awareness on hantavirus infection: A brief review. Biomed Biotechnol Res J 2020;4:274-9
| Introduction|| |
An epidemic or pandemic disease outbreak within a community to several countries, both regional and seasonal, lasting from days to years, has long been known as the major public health threat. Together with the ongoing pandemic of novel coronavirus infection (COVID-19), the 2003 epidemic of the acute respiratory syndrome (SARS), the 1976 HIV/AIDS pandemic starting in the Democratic Republic of the Congo, the 1968 Hong Kong influenza pandemic by the influenza virus subtype H3N2, the 1957–1958 H2N2 Asian influenza, the 1918–1920 H1N1 Spanish influenza, and the 1889–1892 H2N2 Russian influenza are still fiercely to the human civilization.,, Along the last 100 years, several legislative bodies such as the Public Health Emergency of International Concern, the World Health Organization, the Centers for Disease Control and Prevention (CDC), and lots of research groups led by the epidemiologists/virologists/health professionals have been working very hard to protect humans against the dreadful impact of such pandemic diseases and to maintain the global public health sustainability with all their efforts to develop antivirals or vaccines; however, a little or no improvement has been noticed indeed except raising the awareness of the viruses among the general people. Besides, re-emergence of dreadful viruses such as the Ebola viruses, yellow fever viruses, Japanese encephalitis viruses, West Nile viruses, chikungunya viruses (CHIKV), Zika viruses (ZIKV), and dengue viruses (DENV) are frequently being reported. In between such re-emerging infectious disease evolution, the hantavirus appeared with its dreadfulness through the impartment of hyperinflammatory syndromes globally, i.e., the hemorrhagic fever with renal syndrome (HFRS) in Eurasia (with 10% fatality) and the hantavirus pulmonary syndrome (HPS) in the United States with approximately 40% fatality., The current review, therefore, attempted to describe a bit about the hantavirus which could be useful for understanding viral pathogenesis as well as their strategy to escape the host immunity. Predictions on the possible outbreak as well as knowing the preventive measures would bring the sound health regulations with a community during any sort of health crisis in mass scale.
Hantaviruses, also referred to as orthohantaviruses (zoonotic viruses) belonging to the Bunyaviridae family, are the antisense (-) single-stranded (ss) RNA viruses (rodent-borne) unlike the other dreadful positive-sense RNA viruses including the ongoing re-emerging COVID-1, and the recently appeared CHIKV from Togaviridae family, ZIKV from Flaviviridae family, and DENV from Flaviviridae family.,,,,, The HFRS, the hyperinflammatory syndromes as stated above, the HPS which is sometimes referred to as the hantavirus cardiopulmonary syndrome (HCPS), and the posterior reversible encephalopathy syndrome (PRES) are quite frequently propagated complications in Europe, Asia, and Africa caused by this virus as has been well known for the last two decades or more. [6,12-14] Interestingly, the hantavirus is known to be a typical disease for the rodents, but there are no complications among those. However, the virus can be disseminated into humans upon touching the bodily fluids of the infected rodent. It is worth to note at this stage that recently, the human-to-human transmission of hantavirus has been reported as well. The first outbreak of hantavirus with the onset of HFRS was reported during the Korean conflict (1950–1953); nevertheless, the virus was still undiscovered., In the late 1970s, the causative agent for triggering HFRS was discovered as the hantavirus.,
Unfortunately, like the other fatal viruses such as CHIKV or DENV let alone the influenza subtypes, till date, no effective vaccine could be developed neither any effective treatment regimen has come out so far against the hantavirus infection. Therefore, besides the other re-emerging viruses, the clinical features and the possible means of infective mechanisms by the hantavirus disease along with its diagnostics and propagation should be taken into account by the health professionals. The history of hantavirus disease surveillance is not that ancient; the scrutiny in the USA actually started in 1993 during an outbreak of severe respiratory illness and the HPS became a nationally noticeable disease in 1995.
Later in 2014, the Council of State and Territorial Epidemiologists stretched the national reporting of laboratory-confirmed hantavirus infections for the inclusion of the HPS and the nonpulmonary hantavirus infection cases in 2015. Indeed, the zoonotic hantavirus infection is easily communicable from the rodents to humans (especially working in the forest areas) causing serious respiratory diseases, which needs an immediate global attention, since many of the stated recently re-emerging viruses along the currently pandemic COVID-19 appeared to be distinctly fatal.,,,,, The present review simply highlighted the viral transmission, epidemiology, its impact on the host immunity, and finally the preventive measures which can be easily understood by the common people.
| Evolution, Classes of the Hantavirus, and Their Specific Protein Receptors for Cellular Entry|| |
Hantaviruses have been known to coevolve for millions of years with their rodent and insectivore reservoirs as reported by Mir, 2010, through the phylogenetic study, and till date, the hantavirus genus is known to comprise at least 21 species along with more than 30 genotypes. Indeed, the virus (causing hemorrhagic fever) was named as Hantaan virus, after the name of the river Hantan in Korea in 1978; in 1981, a new genus of the virus (causing hemorrhagic fever with renal syndrome, i.e., HFRS) was termed as “hantavirus”, and until 1993, another member was discovered known as the nonpathogenic Prospect Hill virus., The hantavirus outbreak in the four corner region of Southwestern US causing serious respiratory distress in the infected patients led to the discovery of the HPS which was later named as Sin Nombre virus. [6,16-18] The rodent reservoirs of hantaviruses include both Cricetidae (including voles, lemmings of the Northern Hemisphere and the new world mice and rats) and Muridae rodents consisting of the old world mice and rats.
Glycoproteins constitute the major receptor proteins of the hantavirus. As per the genomic characterization, hantavirus genome has been noticed to consist of tripartite negative-sense RNA: (1) the large (L) segment genomic RNA encodes the viral RNA-dependent RNA polymerase (RdR); (2) the medium size (M) segment encodes the viral glycoprotein precursor (GPC) that is further cleaved into two glycoproteins G1 and G2 or Gn/Gc (exposed on the surface of virions); and (3) the small (S) segment encodes the viral nucleocapsid protein (N) to which the three genomic RNAs are complexed inside the virus particle, forming three individual nucleocapsids., Hantavirus glycoproteins are necessary for the virus attachment to the host and the subsequent entry. Besides, the in vitro studies showed that the integrins (β1-3), DAF/CD55, and gC1qR, play major roles as the receptors facilitating the viral attachment for both Old World (HFRS) and New World hantaviruses (HPS) whereas protocadherin-1 has been identified as the receptor for the cellular attachment and entry of the New World hantaviruses. As shown in [Table 1], the pathogenic and nonpathogenic hantaviruses have been reported to use different integrin receptors for their entry into the corresponding host cells; for example, human integrins αIIaβ3 (expressed by platelets) and αvβ3 (expressed by endothelial cells) are employed for entry of HFRS causing hantaviruses, while in case of the nonpathogenic hantaviruses, α5 β1 receptors are used.
| Viral Transmission, Symptoms, and Epidemiology|| |
The phylogenetic tree suggests that cospeciation of hantavirus with their host animals of four different rodent subfamilies appears to influence their ability to cause a specific clinical manifestation in humans. For example, a majority of viruses in Neotominae and Sigmodontinae subfamilies are known to cause severe HPS with high mortality rate (40%–50%). These viruses are distributed throughout North and South America in different rodent species of New World Neotominae and Sigmodontinae rodents. Old World hantaviruses that have coevolved with Murinae rodents cause severe HFRS that primarily affects kidney function with a mortality of 0%–15%. Although the disease caused by Murinae viruses has less mortality rate, it still poses a significant threat to human health due to severity of the disease and the ability of the viruses to cause large-scale epidemics. Among Arvicolinae-borne hantaviruses, only puumala virus (PUUV) causes a mild form of human disease often referred as epidemic nephropathy with a mortality rate of <1%. Interestingly, most other members of this subfamily are non-pathogenic to humans. Until recently, the only exception that did not have a confirmed rodent connection is Thottapalayam virus, which was isolated from an Asian house shrew or musk shrew (Suncus murinus) captured in 1964 during a survey for Japanese encephalitis virus in southern India.
In the rural areas such as forests, fields, and farms, the hantavirus infection usually occurs sporadically. Those habitats seem to be suitable for the virus's rodent hosts usually living in houses, barns, outbuildings, and sheds. Dogs and cats do not directly carry the hantavirus particles; however, they are likely to carry the infected rodents coming into contact with people catching those animals. The Sin Nombre hantavirus (mediated by the host, deer mouse, i.e., Peromyscus maniculatus) has been reported to be a major case of hantavirus infections in the US, Canada, and in the Latin American countries. The white-footed mouse usually triggers the New York hantavirus, which results in HPS cases. The third major vector is the cotton rat, resulting in the Black Creek hantavirus within the southeastern portion of the US., This is to be mentioned that the supreme causative agent of HFRS in Europe is known to be the PUUV which are carried by the bank vole, i.e., Clethrionomys glareolus. It is important to note that the PUUV-associated morbidities are significant; however, the mortality rates score <1% on an average.
There are several evidences that people can be infected with hantaviruses through inhalation of aerosolized excreta (feces, urine, or saliva) produced by infected rodents.,, Infection with hantavirus fever is usually visible with the early symptoms of relatively high body temperature (39°C), myalgia, vomiting, nausea, headache, and abdominal pain as has been found in a clearly hantavirus-infected forestry worker. Dizziness, nonproductive cough, malaise, diarrhea, and lightheadedness and the gastrointestinal (GI) complications are closely associated with the viral infection. Moreover, arthralgia, back pain, and abdominal pain can be noticed; more dreadful situations such as the conjunctival, cerebral, and GI hemorrhages are even not unlikely.,, This is to be noted that HFRS is the major hantavirus-induced disease syndrome in Asia and Europe, whereas HPS is noticed to be dominating within the United States and Latina America.
Due to hantavirus infection, namely in the HPS and HFRS cases, the inflammatory responses accord to the pulmonary vascular leakage that eventually leads to the hypoxic respiratory failure or cardiogenic shock and hence bringing the morbidity and mortality, which, in turn, imparts high mortality rates. As stated earlier, the strains of hantavirus resulting in HFRS were detected primarily in Asia and Europe; the strain resulting in HPS (flu-like symptoms such as fever, chills, myalgia, and vomiting) was first noted in the United States followed by its propagation along the North and Latin America.,, The geographic distribution and host range of novel hantaviruses has also been reported along Africa and the Indian Ocean., The epidemic seasonal predominance is pragmatic, especially summer and to some extent to autumn or winter., The HPS was first noted in Argentina (in 1995) during an outbreak in the Andean region of Patagonia, which led to the categorization of the hantavirus into the Andes virus (ANDV), which was unique among hantaviruses since it could be transmitted from person to person as has been unraveled from the study of target-specific whole-genome sequencing.
| Hantavirus Pathogenesis and the Host Immunity|| |
In the hantavirus-infected humans, the vascular endothelial cells are supposed to be the main target by the viral particles. Furthermore, the epithelial cells, mononuclear phagocytes, and follicular dendritic cells (DC) are invaded by the viruses. Hantavirus infection has been reported to trigger an elevated immune response including substantial cytokine activation (interleukin-15 [IL-15], IL-15Rα, type I interferons [IFNs], IL-12, IL-15, IL-18, and IL-21) and the commencement of the cytotoxic lymphocytes [Figure 1]. A jerk in the response within the granulocyte (neutrophils), natural killer (NK) cells, especially activated by the increased level of IL-15 (producing the antiviral IFN-γ and pro-inflammatory cytokines such as tumor necrosis factor [TNF]), and the elevation in the CD8+ and CD4+ T-cell responses has also been noticed. [7,23-25] More specifically, the increased levels of IL-6 have been noticed to be inked with severity not only with the infection by hantavirus but also the Andes and the PUUVs. Upon infection, an increased level of the intercellular adhesion molecule 1 (ICAM-1), the ligand required for the lymphocyte function-associated antigen 1 (LFA-1), have been noticed to be expressed on the cell surface, resulting in the lymphocyte adhesion to the endothelial cells, activation of the NK cells (the hiscompatibility antigen, α chain E; i.e., HLA-E serves as a ligand for the activating NK cell receptor NKG2C expressing CD57), and release of granules [Figure 1].,
|Figure 1: Hantavirus pathogenesis and immunity features. In the hantavirus-infected individuals, the major targets are the vascular endothelial cells, mononuclear phagocytes (MNP), and follicular dendritic cells (DC). The virus is known to cause two related hyperinflammatory syndromes: HFRS, and HPS. Viral infection usually leads to an elevated production of cytokines and cytotoxic lymphocytes with the onset of several typical flu-like symptoms, hypotension, acute shock, vascular leakage, kidney failure, and even lung failure symptoms. As stated in the text, the most common causative agent of HFRS in Europe is PUUV whereby the MNP, granulocyte, natural killer (NK) cell, as well as CD8+ and CD4+ T-cell responses have been noticed. The responses regarding B cells, the activation of the mucosal-associated invariant T (MAIT) cells, and the production of innate lymphoid cells (ILCs) in acute PUUV infection are still obscure. Monocytes, macrophages, and the dendritic cells (DCs) may protect the host from viral antigens binding from T cells and also may produce IFN-1 and other cytokines and hence can trigger the virus-specific immune responses|
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As stated above, the hantaviruses are principally transmitted via inhalation, and therefore, the monocyte-derived cells and DCs present in the respiratory compartments of humans are of particular significance in the viral pathogenesis since pulmonary dysfunction (the major syndrome of HPS) is also associated with HFRS. After infection, an increased level of the intercellular adhesion molecule 1 (ICAM-1), the ligand required for the lymphocyte function-associated antigen 1 (LFA-1), have been noticed to be expressed on the cell surface, resulting in the lymphocyte adhesion to the endothelial cells, activation of the NK cells (especially CD56dim and the atypical CD56neg NK cells), and release of granules.,,, However, it is still not clear whether and to what extent the activation of NK cells may impart to the hantavirus disease pathology. At the early state of hantavirus infection, more increase in the CD8+ T cells has been noticed over the CD4+ T cells (which went normal at the recuperative phase); at the acute phase of infection, CD8+ T cells were found to express Ki67 (suggestive of cellular proliferation), CD38 (possibly required for calcium signaling to trigger granule release as stated earlier), and HLA-DR (the MHCII consisting of T cell receptor. In addition, this is to be mentioned that HERS is associated with elevated production of IL-6, IL-8, IL-10, TNF, and IFN-γ.
| Treatment and Prevention of the Viral Infection|| |
Provisionally some useful treatments have been suggested involving the (1) use of anti-IL-15 antibodies (to suppress the activation of NK cells required for the hantavirus infection progression); (2) the anti-IL-6R therapeutic strategies; and (3) by immune chemotherapy to treat the familial hemophagocytic lymphohistiocytosis (FHL), an immunodeficiency syndrome affecting infants or young children. However, till date, there is no Food and Drug Administration (FDA)-approved preventive vaccine for HFRS or HPS. Rather, the annual increase of HFRS patients may relate to the increased awareness by the medical professionals and to the climate change. This is noteworthy that the European Union (EU)-funded VIZIER project (Comparative Structural Genomics of Viral Enzymes Involved in Replication) has the mission to develop the antiviral therapeutic strategies, i. e., specifically for the RNA viruses such as the arenaviruses and bunyaviruses. Nevertheless, since there is no appropriate vaccination or effective chemotherapy against the hantavirus infection, proper prevention measures should be taken by the community members to stop the viral outbreaks.
As a part of public awareness, the implication of the sociocultural studies/survey to assess knowledge, attitudes, and practices (KAP) of a specific community regarding the fatality of hantavirus infection as well as its prevention can be an important measure stop the spread of hantavirus infection. It is worth to mention that such KAP surveys may help also for the interventions for DENV, ZIKV, CHIKV, and malarial viral infections. Some suggested preventive practices for the forestry workers include to clean and taking out the trashes wearing clean gloves and masks, picking up waste remains, wood trashes, keeping trash in rodent-resistant containers, sealing cracks in the home, appropriate mopping, keeping food and water in clean containers with sterilized lids, and preserving grains in the sealed containers.,
| Conclusion|| |
Hantavirus is actually maintained in nature and transmitted to humans via the rodents. In humans, the hantaviruses, inclusive of Hantaan virus, Dobrava virus, PUUV, Sin Nombre virus and ANDV, trigger the hemorrhagic fever with renal syndrome (HFRS) and the HPS globally (HFRS in Europe and Asia whereas HPS mainly in the United States) reported by many groups of researchers. The morbidity and mortality have been assessed so far to be significant; however, appropriate vaccines, antivirals, and the accurate immunotherapy are still lacking. As discussed in the current review, although the theoretical knowledge regarding the epidemics of hantavirus is quite updated, still there may be a knowledge breach on the subject of the viral route of transmission. Moreover, the majority of the world population perhaps is unaware to realize the risk allied with this apparently uncommon virus. As discussed in this review, all inclusive control and preventive actions should include the purging of the rodents and restriction of their access to residences, awareness on sanitation to the general people, reduction of shelters for rats and mice, etc., Some reported physical restrictions as barriers to cleaning patios and moving accumulations of waste materials, which should be considered in future interventions. Since most respondents had heard of hantavirus through community members, future interventions should be community based and involve those who have experienced the disease as information disseminators.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Lin Q, Zhao S, Gao D, Lou Y, Yang S, Musa SS, et al
. A conceptual model for the coronavirus disease 2019 (COVID-19) outbreak in Wuhan, China with individual reaction and governmental action. Int J Infect Dis 2020;93:211-6.
Eisinger RW, Fauci AS. Ending the HIV/AIDS pandemic. Emerg Infect Dis 2018;24:413-6.
Poole DN, Escudero DJ, Gostin LO, Leblang D, Talbot EA. Responding to the COVID-19 pandemic in complex humanitarian crises. Int J Equity Health 2020;19:41.
Paixão ES, Teixeira MG, Rodrigues LC. Zika, chikungunya and dengue: The causes and threats of new and re-emerging arboviral diseases. BMJ Global Health 2018;3:e000530.
Muco E, Hasa A, Rroji A, Kushi A, Puca E, Kraja D. Posterior reversible encephalopathy syndrome in a patient with hemorrhagic fever with renal syndrome. Case Rep Infect Dis 2020;2020:1017689.
Klingström J, Smed-Sörensen A, Maleki KT, Solà-Riera C, Ahlm C, Björkström NK, et al
. Innate and adaptive immune responses against human Puumala virus infection: Immunopathogenesis and suggestions for novel treatment strategies for severe hantavirus-associated syndromes. J Intern Med 2019;285:510-23.
Noor R, Ahmed T. Zika virus: Epidemiological study and its association with public health risk. J Infect Public Health 2018;11:611-6.
Zhao L, Alto BW, Shin D. Transcriptional profile of aedes aegypti leucine-rich repeat proteins in response to zika and chikungunya viruses. Int J Mol Sci 2019;20:615.
Noor R. Re-emergence of dengue virus in Bangladesh: Current fatality and the required knowledge. Tzu Chi Med J 2020;32:227-33. [Full text]
Alonso DO, Pérez-Sautu U, Bellomo CM, Prieto K, Iglesias A, Coelho R, et al
. Person-to-person transmission of Andes virus in hantavirus pulmonary syndrome, argentina, 2014. Emerg Infect Dis 2020;26:756-9.
Puca E, Pilaca A, Pipero P, Bino S, Kote M, Rogozi E, et al
. Hemorrhagic fever with renal syndrome complicated by orchitis. Virol Sin 2011;26:285-8.
McKinney AM, Short J, Truwit CL, McKinney ZJ, Kozak OS, SantaCruz KS, et al
. Posterior reversible encephalopathy syndrome: Incidence of atypical regions of involvement and imaging findings. Am J Roentgenol 2007;189:904-12.
Lee HW, Lee PW, Baek LJ, Chu YK. Geographical distribution of hemorrhagic fever with renal syndrome and hantaviruses. In: Calisher CH, editors. Hemorrhagic Fever with Renal Syndrome, Tick-and Mosquito-Borne Viruses. Archives of Virology Supplementum. Vol. 1. Vienna: Springer; 1990.
Vaheri A, Strandin T, Hepojoki J, Sironen T, Henttonen H, Mäkelä S, et al
. Uncovering the mysteries of hantavirus infections. Nat Rev Microbiol 2013;11:539-50.
Harris C, Armién B. Sociocultural determinants of adoption of preventive practices for hantavirus: A knowledge, attitudes, and practices survey in Tonosí, Panama. PLoS Negl Trop Dis 2020;14:e0008111.
Mir MA. Hantaviruses. Clin Lab Med 2010;30:67-91.
Mittler E, Dieterle ME, Kleinfelter LM, Slough MM, Chandran K, Jangra RK. Hantavirus entry: Perspectives and recent advances. Adv Virus Res 2019;104:185-224.
Gavrilovskaya IN, Gorbunova EE, Mackow NA, Mackow ER. Hantaviruses direct endothelial cell permeability by sensitizing cells to the vascular permeability factor VEGF, while angiopoietin 1 and sphingosine 1-phosphate inhibit hantavirus-directed permeability. J Virol 2008;82:5797-806.
Rabemananjara HA, Raharinosy V, Razafimahefa RM, Ravalohery JP, Rafisandratantsoa JT, Andriamandimby SF, et al
. Human exposure to hantaviruses associated with rodents of the murinae subfamily, madagascar. Emerg Infect Dis 2020;26:587-90.
Park KH, Kang YU, Kang SJ, Jung YS, Jang HC, Jung SI. Experience with extrarenal manifestations of hemorrhagic fever with renal syndrome in a tertiary care hospital in South Korea. Am J Trop Med Hyg 2011;84:229-33.
Rasmuson J, Lindqvist P, Sörensen K, Hedström M, Blomberg A, Ahlm C. Cardiopulmonary involvement in Puumala hantavirus infection. BMC Infect Dis 2013;13:501.
Jost S, Altfeld M. Control of human viral infections by natural killer cells. Annu Rev Immunol 2013;31:163-94.
Björkström NK, Lindgren T, Stoltz M, Fauriat C, Braun M, Evander M, et al
. Rapid expansion and long-term persistence of elevated NK cell numbers in humans infected with hantavirus. J Exp Med 2011;208:13-21.
Khaiboullina SF, Levis S, Morzunov SP, Martynova EV, Anokhin VA, Gusev OA, et al
. Serum cytokine profiles differentiating hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. Front Immunol 2017;8:567.
Charrel RN, Coutard B, Baronti C, Canard B, Nougairede A, Frangeul A, et al
. Arenaviruses and hantaviruses: From epidemiology and genomics to antivirals. Antiviral Res 2011;90:102-14.
Whiteman A, Mejia A, Hernandez I, Loaiza JR. Socioeconomic and demographic predictors of resident knowledge, attitude, and practice regarding arthropod-borne viruses in Panama. BMC Public Health 2018;18:1261.