The MCC composite tree (Appendix Figure
) shows that all 38 samples from HPS patients and from rodents captured near human cases were related to ARAV or JUQV groups. Moreover, ARAV lineages obtained in the Central Plateau or southeastern region grouped in a robust monophyletic group independent of human or rodent origin. This finding reinforces the probability of zoonotic origin of human cases from a rodent-borne zoonotic pool and supports the view that closely related hantavirus lineages associated with distinct rodent species may be experiencing cross-species transmission (spillover) (13,18
). ARAV appears to have dispersed from the cerrado region toward the southeast throughout São Paulo, as indicated by the basal position of the SS_DF_Nlas cluster in the MCC composite tree (Appendix Figure
). JUQV dispersed across the southern temperate Araucaria pine forests and along the Atlantic rain forest, as shown by the basal position of SE_SC_Oni_1.
Several associations in the ARAV clade suggest movement of infected persons or dispersal of infected rodents. TB_SP_Hsp_18, which was isolated from a human case of HPS, was closely related to viruses from the Central Plateau. JU_SP_Hsp_11, ST_SP_Hsp_16, and AR_SP_Hsp_21 from the southeastern region were closely related to CO_GO_Hsp_20 from the Central Plateau. Data also indicated that genetic diversity of JUQV is greater than previously determined. SE_SC_Oni_1 from O. nigripes and AG_SP_Ost_1 from O. stramineus were basal taxa to JUQV with high support but may be the most divergent lineages so far detected. Levels of support in the MCC tree indicated that SG_MG_Nlas_8 and CX_RS_Hsp_22 would always branch from poorly defined nodes in the tree in a basal position relative to ARAV-Pergamino, JUQV, and Oran lineages. These results suggest that SG_MG_Nlas_8 and CX_RS_Hsp_22 may represent distinct lineages linking Argentinean Oran and Pergamino hantaviruses to lineages from which ARAV and JUQV originated.
Rooting of the tree and lineage associations suggest that ARAV and JUQV may have originated from a Necromys
spp.–associated hantavirus from the southern part of South America. This theory supports our finding of 1 N
infected by ARAV (SG_MG_Nlas_9) and another N
infected by a highly divergent lineage (SG_MG_Nlas_8) that outgroups with ARAV and JUQV. Both rodents were collected in São Gotardo in Minas Gerais State, at the edge of the central plains. The role of distinct rodent species as potential reservoirs and sources of human infection in Brazil and South America needs to be better understood. However, our data corroborate reports showing that N
is a reservoir of ARAV, that O
is a reservoir of JUQV, and that rodents transmit hantaviruses to humans (6–8
Rodent behavior is a factor in transmission of hantaviruses to humans, and N
is an opportunistic and aggressive rodent species that is gradually being encroached upon in environments experiencing anthropogenic change in the southeastern region and the Central Plateau of Brazil. Conversely, O
has adapted to the Atlantic and Araucaria pine forests and has been found in lineal natural habitats bordering cultivated areas (5,7,19
). Detection of AG_SP_Ost_1 in O
in the O
–associated JUQV group could be explained by virus spillover because O
is usually not infected with hantaviruses. Sampling also identified RP_SP_Ako_1 in an Akodon
sp. rodent in Ribeirão Preto northwest of São Paulo State. This isolate branches in the tree within a well supported cluster of HPS cases reported in areas >
50 miles of Ribeirão Preto. Distribution of Akodon
spp. rodents includes the pampas grasslands of Argentina, and Bolivia, Paraguay, Uruguay, and southern Brazil. These rodents are known to be associated with hantaviruses in Argentina. Not yet determined is whether an Akodon
sp. is transmitting hantavirus to humans in Ribeirão Preto (west of São Paulo State) and whether this infection was a recent cross-species transmission event from N
Samples we analyzed came from an extensive area that contained natural ecosystems largely degraded as a consequence of intensive agriculture and cattle raising. This region contains nearly one third of the population of Brazil in hundreds of towns and several large cities that grew during the 20th century. Other than agricultural expansion over a pristine environment, explosive and poorly planned urban expansion has also been responsible for degrading surrounding ecosystems. A recent estimate of the short-term rate of evolution of hantaviruses in South America indicates that divergence and spread of ARAV and JUQV is relatively recent, possibly within the past 200 years (13
). Thus, increasing environmental and demographic changes during the past 100 years likely affected the ecology of wild rodent reservoirs and facilitated human infections and the emergence of HPS that we now observe.
Whether ARAV and JUQV differ in pathogenicity is unknown A possible distinction between these 2 groups is that the case-fatality rate in regions where ARAV has been isolated appears to be higher than that for JUQV. Higher case-fatality rates of HPS cases in regions with ARAV (Central Plateau and southeastern region) than in regions with JUQV (southeastern coast and southern region) suggest that ARAV is the most virulent hantavirus detected in Brazil (6,7,19
). However, although ARAV has produced the most severe forms of HPS, many infections with ARAV are benign. This finding was observed in São Paulo State, where a serologic survey in Jardinópolis County showed that 14.3% of 32,000 local inhabitants had IgG antibodies to hantavirus (20
), indicating that many persons were exposed to the hantavirus but did not have severe clinical symptoms. Further study is needed to determine which factors influence the severity of disease manifestation in humans caused by infections with hantaviruses, specifically with ARAV or JUQV (6–8
We have identified the viruses circulating in our study area as ARAV and JUQV. Based on geographic distribution of these viruses and the assumption that no other unknown lineage is causing disease in humans, we suggest that ARAV may be responsible for >50% of HPS cases reported in Brazil. ARAV was associated with areas experiencing greater anthropogenic changes and disorganized human population growth than other more stable areas. ARAV may be the most virulent hantavirus in Brazil.