Many pa­tients with SARS-CoV­‑2 dis­ease suf­fer from (some­times) se­vere neu­ro­log­i­cal con­comi­tants that are pro­longed or even ir­re­versible. The virus can cause dam­age in the brain, but that alone is not it.

We are al­so shocked to see how SARS pa­tients, who have been ar­ti­fi­cial­ly ven­ti­lat­ed for weeks, dare to take their first steps by ex­ert­ing all their strength; and how dis­tressed they are when, de­spite in­ten­sive re­ha­bil­i­ta­tion mea­sures, neu­ro­log­i­cal deficits per­sist, mak­ing re­cov­ery a dis­tant prospect. Most of­ten, pa­tients com­plain about pro­nounced dis­tur­bances in their abil­i­ty to con­cen­trate, learn and re­mem­ber, but al­so about deficits in their at­ten­tion, the dis­play of emo­tions or the cor­rect eval­u­a­tion of the emo­tions of oth­ers. In ad­di­tion, there is chron­ic nerve pain that ex­tends far in­to the spinal cord and dizzi­ness. Ex­treme­ly rare neu­ro­log­i­cal syn­dromes such as cra­nial nerve fail­ure and cor­ti­cal blind­ness can al­so be observed.

Our stud­ies and oth­ers show that just over 13 per­cent of hos­pi­tal­ized neu­ro­log­i­cal­ly in­duced SARS-CoV­‑2 pa­tients have se­ri­ous neu­ro­log­ic com­pli­ca­tions. Pa­tients with neu­rocog­ni­tive symp­toms had near­ly 40 per­cent high­er mor­tal­i­ty com­pared with SARS-CoV­‑2 pa­tients with­out con­comi­tant neu­rocog­ni­tive dis­ease. In stud­ies of pa­tients who were not hos­pi­tal­ized, we showed — at least tem­porar­i­ly present — that im­paired con­cen­tra­tion and think­ing were present in up to 84 per­cent of SARS-CoV­‑2 cases.

Whether and when the neu­rocog­ni­tive signs of the dis­ease will dis­ap­pear again, we can­not (yet) pre­dict. But we see that nu­mer­ous pa­tients who al­ready be­came sick dur­ing the first thresh­old pe­ri­od in spring 2020 are still not symp­tom-free today.

But why does SARS-CoV­‑2 virus en­ter the brain any­way? Mean­while, to­geth­er with our col­leagues in Den­mark and Cana­da, we have three ex­pla­na­tions for this:

• The sim­plest ex­pla­na­tion would be that in a se­vere course with ar­ti­fi­cial ven­ti­la­tion, the brain can­not be sup­plied with suf­fi­cient oxy­gen for a pro­longed pe­ri­od. The re­sult­ing brain dam­age could at least part­ly ex­plain the wide spec­trum of symp­toms. This is con­tra­dict­ed by the fact that neu­ro­log­i­cal se­que­lae al­so oc­cur in pa­tients who have not had a se­vere course of the disease.
• Al­ter­na­tive­ly, di­rect dam­age to nerve cells by Sars-CoV­‑2 could be the cause. How­ev­er, in au­top­sies of de­ceased Covid-19 pa­tients, vi­ral RNA has rarely been de­tect­ed in brain cells.
• A third hy­poth­e­sis holds that neu­ro-covid is an im­muno­log­i­cal col­lat­er­al dam­age, sim­i­lar to that oc­cur­ring in oth­er or­gans — pre­sum­ably as a re­sult of a so-called cy­tokine storm.

Ac­cord­ing to our in­ves­ti­ga­tions, the sec­ond and third ex­pla­na­tions are prob­a­bly both cor­rect. Ac­cord­ing to them, the neu­ro­log­i­cal­ly in­duced SARS-CoV­‑2 in­fec­tion is both a di­rect con­se­quence of the in­fec­tion with Sars-CoV­‑2 of sin­gle neu­rons and one of the im­mune sys­tem go­ing astray in the brain.

In our re­cent study, we want­ed to clar­i­fy whether Sars-CoV­‑2 can pen­e­trate brain cells and which re­cep­tors must be present for this to hap­pen. To do this, they used so-called brain organoids, brain-like struc­tures grown from nerve cells in the lab­o­ra­to­ry. The re­sult: Sars-CoV­‑2 pen­e­trates in­to nerve cells in par­tic­u­lar when these con­tain the ACE‑2 re­cep­tor. This leads to func­tion­al dis­or­ders both in the in­fect­ed cell and in neigh­bor­ing neu­rons and struc­tur­al cells con­nect­ed to the cell. If the ACE‑2 re­cep­tor, via which the virus nor­mal­ly en­ters the cells, is blocked on the sur­face of the cul­tured neu­rons, the nerve cell is re­sis­tant to infection.

Us­ing ge­net­i­cal­ly mod­i­fied mice with a high den­si­ty of ACE‑2 re­cep­tors on the sur­face of their neu­rons, we were able to show that the more ACE‑2 re­cep­tors there are on the cell sur­face, the more fre­quent­ly Sars-CoV­‑2 en­ters a nerve cell. Our ear­li­er stud­ies on this have al­so shown that there are dif­fer­ent num­bers of ACE‑2 re­cep­tors on the neu­rons of dif­fer­ent brain regions.

In a third step, we and col­leagues sys­tem­at­i­cal­ly ex­am­ined the brains of three pa­tients who died of SARS-CoV­‑2 for the pres­ence of this vi­ral vari­ant. And in­deed, us­ing a spe­cial stain­ing tech­nique, the spike pro­tein of the virus could be de­tect­ed in­side some neu­rons. How­ev­er, the brain re­gion af­fect­ed by in­fec­tion dif­fered from pa­tient to pa­tient. In ad­di­tion, we took cere­brospinal flu­id (CSF) from the pa­tients’ lum­bar spine and iso­lat­ed the im­mune cells from it. In these, we an­a­lyzed all RNA mol­e­cules, which gives us a pic­ture of which pro­teins are cur­rent­ly need­ed in a cell. This method is tech­ni­cal­ly ex­treme­ly com­plex and can there­fore on­ly be used in iso­lat­ed cas­es of neu­ro­log­i­cal diseases.

We use the method to de­tect com­plex pat­terns of im­mune cell ac­tiv­i­ty. We com­pared the sig­na­tures of im­mune cells of the pa­tients with neu­ro­log­i­cal SARS-CoV­‑2 virus re­sult­ing from this tran­scrip­tome analy­sis with sig­na­tures of im­mune cells in non-in­flam­ma­to­ry brain dis­ease, mul­ti­ple scle­ro­sis and vi­ral encephalitis.

The re­sults are as strik­ing as they are dif­fi­cult to as­sess: So-called ex­haust­ed T cells, a nor­mal­ly ab­sent func­tion­al type of T lym­pho­cytes, are present in large num­bers in the cere­brospinal flu­id of the neu­ro­log­i­cal­ly in­duced SARS-CoV­‑2 pa­tients. In con­trast, this cell state did not oc­cur in the cere­brospinal flu­id of the con­trol groups. The ex­haust­ed T cells be­long to the cell group whose task is to co­or­di­nate the de­fense against vi­ral in­va­sion. They are called ex­haust­ed be­cause they have ex­haust­ed their reper­toire of de­fense-pro­mot­ing mea­sures and are fig­u­ra­tive­ly at the end of their rope. Mono­cytes show a sim­i­lar phe­nom­e­non: these cells are al­so an im­por­tant com­po­nent of the im­muno­log­i­cal os­cil­la­to­ry sys­tem and con­tin­ue to dif­fer­en­ti­ate dur­ing the course of an im­mune re­sponse. But ex­act­ly the op­po­site is the case with the mono­cytes of the neu­ro­log­i­cal­ly in­duced SARS-CoV­‑2 pa­tients. These im­mune cells had vir­tu­al­ly re­vert­ed to their orig­i­nal un­dif­fer­en­ti­at­ed state.

We con­clude that the fine­ly tuned im­muno­log­i­cal sys­tem has lost its ba­sis and that the im­mune sys­tem brings it­self to the brink of ex­haus­tion by su­per­flu­ous ac­tion­ism. How­ev­er, we have not yet been able to clar­i­fy why the de­fens­es are ex­haust­ed when Sars-CoV­‑2 ap­par­ent­ly pen­e­trates neu­rons on­ly rel­a­tive­ly rarely.